WO2004113304A1 - Indazole, benzisoxazole, and benzisothiazole kinase inhibitors - Google Patents

Indazole, benzisoxazole, and benzisothiazole kinase inhibitors Download PDF

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Publication number
WO2004113304A1
WO2004113304A1 PCT/US2004/016166 US2004016166W WO2004113304A1 WO 2004113304 A1 WO2004113304 A1 WO 2004113304A1 US 2004016166 W US2004016166 W US 2004016166W WO 2004113304 A1 WO2004113304 A1 WO 2004113304A1
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Prior art keywords
amino
phenyl
indazol
urea
fluoro
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PCT/US2004/016166
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English (en)
French (fr)
Inventor
Yujia Dai
Steven K. Davidsen
Anna M. Ericsson
Kresna Hartandi
Zhiqin Ji
Michael R. Michaelides
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Abbott Laboratories
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Priority claimed from US10/443,254 external-priority patent/US20040235892A1/en
Priority claimed from US10/842,292 external-priority patent/US7297709B2/en
Priority to MXPA05012596A priority Critical patent/MXPA05012596A/es
Priority to AU2004249675A priority patent/AU2004249675B2/en
Priority to JP2006533326A priority patent/JP4810427B2/ja
Priority to AT04776083T priority patent/ATE469888T1/de
Priority to BRPI0410745-4A priority patent/BRPI0410745A/pt
Priority to CN2004800205684A priority patent/CN1826324B/zh
Priority to CA2526430A priority patent/CA2526430C/en
Priority to PL04776083T priority patent/PL1638941T3/pl
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to SI200431481T priority patent/SI1638941T1/sl
Priority to NZ543614A priority patent/NZ543614A/en
Priority to DK04776083.0T priority patent/DK1638941T3/da
Priority to EP04776083A priority patent/EP1638941B1/en
Priority to DE602004027490T priority patent/DE602004027490D1/de
Publication of WO2004113304A1 publication Critical patent/WO2004113304A1/en
Priority to IL171976A priority patent/IL171976A0/en
Priority to HK06109624.9A priority patent/HK1089172A1/xx
Priority to AU2010202984A priority patent/AU2010202984A1/en

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Definitions

  • the present invention relates to compounds which are useful for inhibiting protein tyrosine kinases, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
  • PTKs Protein tyrosine kinases
  • endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, and infantile hemangiomas).
  • inappropriate vascularization e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, and infantile hemangiomas.
  • the identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of tyrosine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable.
  • the identification of methods and compounds that specifically inhibit the function of a tyrosine kinase which is essential for antiogenic processes or the formation of vascular hyperpermeability leading to edema, ascites, effusions, exudates, and macromolecular extravasation and matrix deposition as well as associated disorders would be beneficial.
  • A is selected from the group consisting of indolyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and thienyl;
  • X is selected from the group consisting of O, S, and NR 9 ;
  • R and R are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR a R b )alkoxy, (NR a R b )alkenyl, (NR a R b )alkyl, (NR a R b )alkynyl, (NR a R b )carbonylalkenyl, and (NR a R b )carbonylalkyl;
  • R 3 , R , and R 5 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, and LR 6 ; provided that at least two of R 3 , R 4 , and R 5 are other than LR 6 ;
  • L is selected from the group consisting of (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH2) n and CH 2 C(O)NR 7 , wherein m and n are independently 0 or 1, and wherein each group is drawn with its left end attached to A;
  • R 6 is selected from the group consisting of hydrogen, aryl, cycloalkyl, heterocyclyl, and 1,3-benzodioxolyl wherein the 1,3-benzodioxolyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and (NR c R d )alkyl; R and R are independently selected from the group consising of hydrogen and alkyl;
  • R 9 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NR a R b )alkyl;
  • R a and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl; and R c and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.
  • the present invention provides a compound of formula (II)
  • X is selected from the group consisting of O, S, and NR 9 ;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR a R b )alkoxy, (NR a R b )alkenyl, (NR a R b )alkyl, (NR a R b )carbonylalkenyl, and (NR a R b )carbonylalkyl;
  • R and R are independently selected from the group consisting of hydrogen, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy;
  • L is selected from the group consisting of (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n and CH 2 C(O)NR , wherein m and n are independently 0 or 1, and wherein each group is drawn with its left end attached to the ring substituted with R 3 and R 4 ;
  • R and R are independently selected from the group consising of hydrogen and alkyl;
  • R 9 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NR a R b )alkyl;
  • R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR c R d ;
  • R and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; and
  • R° and R d are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.
  • the present invention provides a compound of formula(I) wherein X is O and A, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in formula (I).
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is O; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and (NR c R d )alkyl; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; and m,
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is O; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and (NR c R d )alkyl; L is
  • R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy;
  • R 3 , R 4 , R 7 , and R 8 are hydrogen; and
  • R c and R d are selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is O; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl; L is
  • the present invention provides a compound of formula(I) wherein X is S and A, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in formula (I).
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d ,
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is S; R 5 is LR ; R 6 is 1,3-benzodioxolyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and (NR c R d )alkyl; L is (CH 2 )mN(R 7 )C(O)N(R 8 )(CH 2 )n; m and n are 0
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is S; R is LR ; R is 1,3-benzodioxolyl; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; and R 3 , R 4 , R 7 , and R 8 are hydrogen.
  • the present invention provides a compound of formula (I) wherein X is NR 9 ; and A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 9 are as defined in formula (I).
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and (NR c R d )alkyl; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; and m
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is NR 9 ; R 5 is LR ; R is 1,3-benzodioxolyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR°R d , and (NR c R d )alkyl; L is (CH2)mN(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is 1,3-benzodioxolyl; L is (CH2) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; R 3 , R 4 , R 7 , and R 8 are hydrogen; and R 9 is selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is O; R 5 is LR 6 ; R 6 is cycloalkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo;
  • L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; and m, n, R c , R d , R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are as defined in formula (I).
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is O; R 5 is LR ; R is cycloalkyl wherein the cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, wherein the cycloalkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; m and n are 0;
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is O; R is LR ; R is cycloalkyl wherein the cycloalkyl is cyclopentyl; L is (CH 2 )mN(R 7 )C(O)N(R 8 )(CH 2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; and R 3 , R 4 , R 7 , and R 8 are hydrogen.
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is cycloalkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo;
  • L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; and m, n, R c , R d , R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are as defined in formula (I).
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is cycloalkyl wherein the cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, wherein the cycloalkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo; L is (CH2) m N(R 7 )C(O)N(R 8 )(CH 2 )loom; m and n are 0;
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is cycloalkyl wherein the cycloalkyl is cyclopentyl; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; and R 3 , R , R 7 , and R are hydrogen.
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is cycloalkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo;
  • L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; and m, n, R c , R d , R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 are as defined in formula (I).
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is cycloalkyl wherein the cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl, wherein the cycloalkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; m and
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is cycloalkyl wherein the cycloalkyl is cyclopentyl; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; R 3 , R 4 , R 7 , and R 8 are hydrogen; and R 9 is selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is O; R 5 is LR 6 ; R is heterocyclyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo; L is
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is O; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of furyl, isoxazolyl, isothiazolyl, oxazolyl, pyridinyl, thiazolyl, and thienyl, wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo; L is (CH 2 )mN(R 7 )C(O)N(R 8 )
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is O; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl is thienyl; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; and R 3 , R 4 , R 7 , and R 8 are hydrogen.
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is heterocyclyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo;
  • L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; and m, n, R c , R d , R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are as defined in formula (I).
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is S; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of furyl, isoxazolyl, isothiazolyl, oxazolyl, pyridinyl, thiazolyl, and thienyl, wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo; L is (CH 2 ) m N(R 7 )C(O)N(R 8
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is S; R is LR ; R is heteocyclyl wherein the heterocyclyl is thienyl; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; and R 3 , R 4 , R 7 , and R 8 are hydrogen.
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is heterocyclyl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR°R d , (NR c R d )alkyl, and oxo;
  • L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; and m, n, R c , R d , R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 are as defined in formula (I).
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl is selected from the group consisting of furyl, isoxazolyl, isothiazolyl, oxazolyl, pyridinyl, thiazolyl, and thienyl, wherein the heterocyclyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo; L is (CH 2 )mN(R 7 )C(O)N(R
  • the present invention provides a compound of formula(I) wherein A is phenyl; X is NR 9 ; R 5 is LR 6 ; R 6 is heterocyclyl wherein the heterocyclyl is thienyl; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH2) n ; m and n are 0; R 1 and R 2 are independently selected from the group consisting of hydrogen and alkoxy; R 3 , R 4 , R 7 , and R 8 are hydrogen; and R 9 is selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a method for inhibiting protein kinase in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
  • the present invention provides a method for treating cancer in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
  • the present invention provides a compound of formula (II) wherein L is CH 2 C(O)NR 7 ; and X, R 1 , R 2 , R 3 , R 4 , R 7 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is CH 2 C(O)NR 7 ; and R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is CH 2 C(O)NR 7 ; and R 1 , R 2 , R 3 , R 4 , R 7 , R 9 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is CH 2 C(O)NR 7 ; R 1 , R 2 , R 3 , R 4 , and R 7 are hydrogen; R 9 is selected from the group consisting of hydrogen and alkyl; R 10 and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is CH 2 C(O)NR 7 ; R 1 , R 2 , R 3 , R 4 , and R 7 are hydrogen; R 9 is selected from the group consisting of hydrogen and alkyl; R 10 and R 11 independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy; and R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is CH 2 C(O)NR 7 ; R 1 , R 2 , R 3 , R 4 , and R 7 are hydrogen; R 9 is selected from the group consisting of hydrogen and alkyl; R 10 and R 11 independently selected from the group consisting of hydrogen, alkyl, halo, and haloalkyl.
  • the present invention provides a compound of formula (II) wherein L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; and m, n, X, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula(II) wherein X is NR 9 ; and L, R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; and m, n, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are hydrogen; R 9 is selected from the group consisting of alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NR a R b )alkyl; and R a , R b , R 1 , R 2 , R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; and R 1 , R 2 , R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) lake; m and n are 0; R 7 and R 8 are
  • R is hydrogen; one of R and R is selected from the group consisting of hydrogen and halo and the other is selected from the group consisting of hydroxy, hydroxyalkyl, and (NR a R b )alkyl; and R a , R b , R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are
  • R is hydrogen; one of R and R is selected from the group consisting of hydrogen and halo and the other is selected from the group consisting of hydroxy, hydroxyalkyl, and (NR a R b )alkyl; one of R 3 and R 4 is hydrogen and the other is selected from the group consisting of alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR C R ; R a and R are independently selected from the group consisting of hydrogen and alkyl; and R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; m and n are 0; R 1 , R 2 , R 3 , R 7 , R 8 , and R 9 are hydrogen; R 4 is selected from the group consisting of hydrogen and halo; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR c R d ; and R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 7 , R 8 , and R 9 are hydrogen; R 4 is selected from the group consisting of hydrogen and halo; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy; and R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 7 , R 8 , and R 9 are hydrogen; R is selected from the group consisting of hydrogen and halo; and R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, halo, and haloalkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; m and n are 0; R 1 , R 2 , R 3 , R 7 , and R 8 are hydrogen; R 9 is alkyl; R 4 is selected from the group consisting of hydrogen and halo; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR°R d ; and R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 7 , and R 8 are hydrogen; R 9 is alkyl; R 4 is selected from the group consisting of hydrogen and halo; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR C R , and aryloxy wherein the aryloxy is phenoxy; and R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; m and n are 0; R 1 , R 2 , R 3 , R 7 , and R 8 are hydrogen; R is alkyl; R is selected from the group consisting of hydrogen and halo; and R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, halo, and haloalkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) addict; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is halo; and R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 , L is (CH 2 ) ffi N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour, m and n are 0, R 7 and R 8 are hydrogen, R 9 is hydrogen, one of R 1 and R 2 is hydrogen and the other is heterocyclylalkoxy; and R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 , L is (CH 2 ) ra N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour, m and n are 0, R 7 and R 8 are hydrogen, R 9 is hydrogen, one of R 1 and R 2 is hydrogen and the other is heterocyclylalkoxy; R and R are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy; and R c and R are independently selected from the group consisting of hydrogen and alkyl
  • the present invention provides a compound of formula (II) wherein X is NR 9 , L is (CH 2 )mN(R 7 )C(O)N(R 8 )(CH 2 )n, m and n are 0, R 7 and R 8 are
  • R is hydrogen, one of R and R is hydrogen and the other is heterocyclylalkoxy wherein the heterocyclyl is selected from the group consisting of morpholinyl, piperidinyl, pyridinyl, pyrrolyl, pyrrolidinyl optionally substituted with oxo, and 3,4,4-trimethyl-2,5- dioxo-1-imidazolidinyl;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy;
  • R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy; and R c and R d are independently
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are
  • R is hydrogen; one of R and R is hydrogen and the other is selected from the group consisting of (NR a R b )carbonylalkenyl and (NR a R b )alkoxy; and R a , R b , R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of (NR a R b )carbonylalkenyl and (NR a R b )alkoxy; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of (NR a R b )carbonylalkenyl and (NR a R b )alkoxy; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and ary
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are
  • R is hydrogen; one of R and R is hydrogen and the other is selected from the group consisting of aryloxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclyloxyalkyl; and R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of aryloxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclyloxyalkyl; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and ary
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is aryloxyalkyl wherein the aryl is phenyl optionally substituted with halo; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) lake; m and n are 0; R 7 and R 8 are
  • R is hydrogen; one of R and R is hydrogen and the other is heterocyclyl wherein the heterocyclyl is selected from the group consisting of pyridinyl and thienyl;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy;
  • R 10 and R l are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy; and
  • R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; m and n are 0; R 7 and R 8 are
  • R is hydrogen; one of R and R is hydrogen and the other is heterocyclylalkyl wherein the heterocyclyl is selected from the group consisting of morpholinyl and piperazinyl wherein the piperazinyl is optionally substituted with alkyl;
  • R 3 and R are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy;
  • R 10 and R u are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy; and
  • R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are
  • R is hydrogen; one of R and R is hydrogen and the other is heterocyclyloxyalkyl wherein the heterocyclyl is pyridinyl;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy;
  • R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy; and
  • R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of alkoxy, alkoxyalkoxy, and alkyl; and R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; one of R 1 and R 2 is hydrogen and the other is selected from the group consisting of alkoxy, alkoxyalkoxy, and alkyl; R 3 and R 4 are independently selected from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy;
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; and R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; one of R 3 and R 4 is hydrogen and the other is selected from the group consisting of alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; and R 10 and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) addict; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; one of R 3 and R 4 is hydrogen and the other is selected from the group consisting of alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; and R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy; and R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; R 3 and R 4 are hydrogen; and R 10 and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; R 3 and R 4 are hydrogen; and R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy; and R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is NR 9 ; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; m and n are 0; R 7 and R 8 are hydrogen; R 9 is hydrogen; R 1 and R 2 are hydrogen; R 3 and R 4 are alkyl; and R 10 and R 11 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , and aryloxy wherein the aryloxy is phenoxy; and R c and R d are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR a R b )alkoxy, (NR a R b )alkenyl, (NR a R b )alkyl, (NR a R b )carbonylalkenyl, and (NR a R b )carbonylalkyl; and X, L, R a , R b , R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula(II) wherein X is O and L, R 1 , R 2 , R 3 , R 4 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; and m, n, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR a R b ; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) endeavour; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is heterocyclylalkoxy; R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R ° and R are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR a R b ; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 )n; m and n are 0; R 1 is heterocyclylalkoxy wherein the heterocyclyl is morpholinyl; R 2 , R 3 , R , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is O; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula(II) wherein X is O
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; and m, n, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 10 , and R 11 are as defined in formula (II).
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 1 and R u are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR a R b ; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; and R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, halo, and haloalkyl.
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is heterocyclylalkoxy; R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR a R b ; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is heterocyclylalkoxy wherein the heterocyclyl is morpholinyl; R , R , R , R , and R are hydrogen; R and R are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a compound of formula (II) wherein X is S; L is (CH 2 ) m N(R 7 )C(O)N(R 8 )(CH 2 ) n ; m and n are 0; R 1 is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R 2 , R 3 , R 4 , R 7 , and R 8 are hydrogen; R 10 and R 11 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR a R b , and aryloxy wherein the aryloxy is phenoxy; and R a and R b are independently selected from the group consisting of hydrogen and alkyl.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (II), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a method for inhibiting protein kinase in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (II), or a therapeutically acceptable salt thereof.
  • the present invention provides a method for treating cancer in a patient in recognized need of such treatment comprising administering to the patient a therapeutically acceptable amount of a compound of formula (II), or a therapeutically ' acceptable salt thereof.
  • alkenyl refers to a straight or branched chain group of one to six carbon atoms containing at least one carbon-carbon double bond.
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
  • alkoxyalkoxy refers to an alkoxy group attached to the parent molecular moiety through another alkoxy group.
  • alkoxyalkyl refers to an alkyl group substituted with at least one alkoxy group.
  • alkoxycarbonyl refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.
  • alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon of one to six carbon atoms. Preferred alkyl groups of the present invention are of one to three carbon atoms. Most preferred alkyl groups are methyl and ethyl.
  • alkylcarbonyl refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkylsulfonyl refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.
  • aryl refers to a phenyl group, or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings is a phenyl group.
  • Bicyclic fused ring systems are exemplified by a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group.
  • Aryl groups include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • the aryl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR°R d , (NR c R d )alkyl, and oxo; wherein the second aryl group, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl can be further optionally substituted with one, two
  • arylalkyl refers to an alkyl group substituted with at least one aryl group.
  • arylcarbonyl refers to an aryl group attached to the parent molecular moiety through a carbonyl group.
  • arylalkoxy refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxygen atom.
  • aryloxyalkyl refers to an aryloxy group attached to the parent molecular moiety through an alkyl group.
  • arylsulfonyl refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.
  • carbonyl refers to -C(O)-.
  • cyano refers to -CN.
  • cycloalkenyl refers to a non-aromatic cyclic or bicyclic ring system having three to ten carbon atoms and one to three rings, wherein each five- membered ring has one double bond, each six-membered ring has one or two double bonds, each seven- and eight-membered ring has one to three double bonds, and each nine-to ten- membered ring has one to four double bonds.
  • cycloalkenyl groups include, but are not limited to, cyclohexenyl, octahydronaphthalenyl, and norbornylenyl.
  • cycloalkyl refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring system having three to twelve carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[3.1.1]heptyl, and adamantyl.
  • the cycloalkyl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR c R d , (NR c R d )alkyl, and oxo.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl group substituted by one, two, three, or four halogen atoms.
  • haloalkylsulfonyl refers to a haloalkyl group attached to the parent molecular moiety through a sulfonyl group.
  • heterocyclyl represents a monocyclic, bicyclic, or tricyclic ring system wherein one or more rings is a four-, five-, six-, or seven-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Monocyclic ring systems are exemplified by any 3- or 4- membered ring containing a heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the 3- and 4-membered rings have no double bonds, the 5- membered ring has from 0-2 double bonds and the 6- and 7-membered rings have from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine,
  • Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to phenyl ring, a monocyclic cycloalkyl group as defined herein, a monocyclic cycloalkenyl group, as defined herein, or another monocyclic heterocyclyl ring system.
  • bicyclic ring systems include but are not limited to, benzimidazole, benzothiazole, benzothiophene, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, dihydrobenzimidazole, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, and thiopyranopyridine.
  • Tricyclic rings systems are exemplified by any of the above bicyclic ring systems fused to a phenyl ring, a monocyclic cycloalkyl group as defined herein, a monocyclic cycloalkenyl group as defined herein, or another monocyclic heterocyclyl ring system.
  • tricyclic ring systems include, but are not limited to, acridine, carbazole, carboline, dibenzofuran, dibenzothiophene, naphthofuran, naphthothiophene, oxanthrene, phenazine, phenoxathiin, phenoxazine, phenothiazine, thianthrene, thioxanthene, and xanthene.
  • Heterocyclyl groups can be attached to the parent molecular moiety through a carbon atom or a nitrogen atom in the group.
  • heterocyclyl groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR c R d , (NR c R d )alkyl, and oxo; wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl can be further optionally substituted with one,
  • heterocyclylalkoxy refers to a heterocyclyl group attached to the parent molecular moiety through an alkoxy group.
  • heterocyclylalkyl refers to an alkyl group substituted with at least one heterocyclyl group.
  • heterocyclyloxy refers to a heterocyclyl group attached to the parent molecular moiety through an oxygen atom.
  • heterocyclyloxyalkyl refers to an alkyl group substituted with at least one heterocyclyloxy group.
  • heterocyclylsulfonyl refers to a heterocyclyl group attached to the parent molecular moiety through a sulfonyl group.
  • hydroxy refers to -OH.
  • hydroxyalkoxy refers to a hydroxy group attached to the parent molecular moiety through an alkoxy group.
  • hydroxyalkyl refers to an alkyl group substituted with at least one hydroxy group.
  • nitro refers to -NO 2 .
  • (NR R )alkenyl represents an alkenyl group substituted with at least one -NR a R b group.
  • (NR a R b )alkoxy represents an -NR a R b group attached to the parent molecular moiety through an alkoxy group.
  • (NR a R b )alkyl represents an alkyl group substituted with at least one -NR a R b group.
  • (NR a R b )alkynyl represents an alkynyl group substituted with at least one -NR a R b group.
  • (NR a R b )carbonyl represents an (NR a R b ) group attached to the parent molecular moiety through a carbonyl group.
  • (NR a R b )carbonylalkenyl represents an alkenyl group substituted with at least one (NR a R b )carbonyl group.
  • (NR a R b )carbonylalkyl represents an alkyl group substituted with at least one (NR a R b )carbonyl group.
  • R c and R d represent two groups, R c and R d , which are attached to the parent molecular moiety through a nitrogen atom.
  • R c and R d are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein the aryl, the aryl part of the arylalkyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl can be further optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, cyano, halo, haloalkyl, haloalkoxy, nitro, and oxo.
  • (NR c R d )alkyl represents an alkyl group substituted with at least one -NR c R d group.
  • sulfonyl refers to -SO2.
  • the compounds of the present invention can exist as therapeutically acceptable salts.
  • the tenn "therapeutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting an -NR a R group with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate,trifluoroacetate, phosphate, glutamate, bicarbon
  • -NR a R groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • the present compounds can also exist as therapeutically acceptable prodrugs.
  • therapeutically acceptable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • prodrug refers to compounds which are rapidly transformed in vivo to parent compounds of formula (I) or (II) for example, by hydrolysis in blood.
  • compositions which include therapeutically effective amounts of compounds of formula (I) or (II), or therapeutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of formula (I) and (II) and therapeutically acceptable salts thereof are as described above.
  • the carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recepient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of formula (I) or (II), or a therapeutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.5mg to lg, preferably lmg to 700mg, more preferably 5mg to lOOmg of a compound of formula (I) or (II), depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetennined amount of an active ingredient per dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical
  • compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compounds of the present invention can be administered using conventional drug delivery technology, for example, intra-arterial stents.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders are prepared by cumminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt and/or
  • absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided.
  • Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.
  • the compounds of formula (I) and (II), and therapeutically acceptable salts thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phophatidylcholines.
  • the compounds of formula (I) and (II), and therapeutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone; polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil- in-water cream base or a water-in oil base.
  • Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles, and mouth washes.
  • Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops include aqueous or oil solutions of the active ingredient.
  • Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • an effective amount of a compound of formula (I) or (II) for the treatment of neoplastic growth, for example colon or breast carcinoma will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or (II), or a therapeutically acceptable salt thereof, and the use of at least one other cancer treatment method.
  • combination therapies according to the present invention comprise the administration of at least one other pharmaceutically active agent, preferably an anti- neoplastic agent.
  • the compound(s) of formula (I) or (II) and the other pharmaceutically active agent(s) may be administered together or separately and when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of formula (I) or (II) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compounds of formula (I) or (II), or therapeutically acceptable salts thereof, and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies.
  • the other anti-cancer therapy is at least one additional chemotherapeutic therapy including administration of at least one anti-neoplastic agent.
  • the administration in combination of a compound of formula (I) or (II), or therapeutically acceptable salts thereof, with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one anti- neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.
  • Anti-neoplastic agents useful in combination with the compounds and salts of formula (I) or (II) include the following:
  • cell cycle specific anti-neoplastic agents including, but not limited to, diterpenoids such as paclitaxel and its analog docetaxel; vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine; epipodophyllotoxins such as etoposide and teniposide; fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine; antimetabolites such as allopurinol, fludurabine, methotrexate, cladrabine, cytarabine, mercaptopurine, and thioguanine; and camptothecins such as 9-amino camptothecin, irinotecan, topotecan, CPT- 11, and the various optical forms of 7-(-4-methylpiperazino-methylene)-10,l 1-ethylenedioxy- 20-camptothecin; (2) cytotoxic chemotherapeutic agents including, but not limited to, alkylating agents such
  • anti-estrogens such as tomixefen, toremifene, raloxifene, droloxifene, and iodoxyfene
  • progesterogens such as megastrol acetate
  • aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane
  • antiandrogens such as flutamide, nilutamide, bicalutamide, and cyproterone acetate
  • LHRH agonists and antagonists such as goserelin acetate and luprolide, testosterone 5 -dihydroreductase inhibitors such as finasteride
  • metallopreteinase inhibitors such as marimastat
  • antiprogestogens urokinase plasminogen activator receptor function inhibitors
  • growth factor function inhibitors such as inhibitors of the functions of hepatocyte growth factor; erb-B
  • the potency of compounds can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., synthetic peptide (Z. Songyang et al., Nature. 373 :536-539) by a test compound relative to control.
  • an exogenous substrate e.g., synthetic peptide (Z. Songyang et al., Nature. 373 :536-539)
  • the coding sequence for the human KDR intra-cellular domain was generated through PCR using cDNAs isolated from HUVEC cells. A poly-His6 sequence was introduced at the N-terminus of this protein as well. This fragment was cloned into transfection vector pVL1393 at the Xba 1 and Not 1 site. Recombinant baculovirus (BV) was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified through Western analysis. For protein production, SF-9 cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at 0.5 plaque forming units per cell (MOI). Cells were harvested at 48 hours post infection.
  • MOI plaque forming units per cell
  • X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCI, 10% glycerol, 1% Triton X-100, ImM PMSF, lO ⁇ g/ml aprotinin, 1 ⁇ g/ml leupeptin) to the cell pellet from IL of cell culture.
  • the lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4 °C.
  • the cell lysate was applied to a 5 ml NiCi2 chelating sepharose column, equilibrated with 50 mM HEPES, pH7.5, 0.3 M NaCI.
  • KDR was eluted using the same buffer containing 0.25 M imidazole. Column fractions were analyzed using SDS-PAGE and an ELISA assay (below) which measures kinase activity. The purified KDR was exchanged into 25mM HEPES, pH7.5, 25mM NaCI, 5 mM DTT buffer and stored at -80 °C.
  • KDR KDR at IC50's between about 0.003 ⁇ M and about 40 ⁇ M.
  • Preferred compounds inhibited KDR at IC50's between about 0.003 ⁇ M and about 0.1 ⁇ M.
  • the coding sequence for the human Tie-2 intra-cellular domain (aa775-l 124) was generated through PCR using cDNAs isolated from human placenta as a template.
  • Recombinant BV was plaque purified and verified through Western analysis.
  • SF-9 insect cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at MOI of 0.5. Purification of the His-tagged kinase used in screening was analogous to that described for KDR.
  • the baculoviral expression vector pVL1393 (Phar Mingen, Los Angeles, CA) was used. A nucleotide sequence encoding poly-His6 was placed 5' to the nucleotide region encoding the entire intracellular kinase domain of human Flt-1 (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was generated through PCR using cDNA libraries isolated from HUVEC cells. The histidine residues enabled affinity purification of the protein as a manner analogous to that for KDR and ZAP70. SF-9 insect cells were infected at a 0.5 multiplicity and harvested 48 hours post infection.
  • EGFR Tyrosine Kinase Source EGFR was purchased from Sigma (Cat # E-3641 ; 500 units/50 ⁇ L) and the EGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat # PF011-100).
  • the baculo viral expression vector used was pVL1393. (Pharmingen, Los Angeles, Ca.)
  • the nucleotide sequence encoding amino acids M(H)6 LVPR 9 S was placed 5' to the region encoding the entirety of ZAP70 (amino acids 1-619).
  • the nucleotide sequence encoding the ZAP70 coding region was generated through PCR using cDNA libraries isolated from Jurkat immortalized T-cells. The histidine residues enabled affinity purification of the protein (vide infra).
  • the LVPR 9 S bridge constitutes a recognition sequence for proteolytic cleavage by thrombin, enabling removal of the affinity tag from the enzyme.
  • SF- 9 insect cells were infected at a multiplicity of infection of 0.5 and harvested 48 hours post infection.
  • Lck, Fyn, Src, Blk, Csk, and Lyn, and truncated forms thereof may be commercially obtained (e.g., from Upstate Biotechnology Inc. (Saranac Lake, N.Y) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) or purified from known natural or recombinant sources using conventional methods.
  • Enzyme linked Immunosorbent Assay For PTKs Enzyme linked immunosorbent assays (ELISA) were used to detect and measure the presence of tyrosine kinase activity. The ELISA were conducted according to known protocols which are described in, for example, Voller, et al., 1980, "Enzyme-Linked Immunosorbent Assay," In: Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp 359-371 Am. Soc. of Microbiology, Washington, D.C.
  • the disclosed protocol was adapted for determining activity with respect to a specific PTK.
  • preferred protocols for conducting the ELISA experiments is provided below. Adaptation of these protocols for determining a compound's activity for other members of the receptor PTK family, as well as non-receptor tyrosine kinases, are well within the abilities of those in the art.
  • a universal PTK substrate e.g., random copolymer of poly(Glu 4 Tyr), 20,000-50,000 MW
  • ATP typically 5 ⁇ M
  • PGTPoly (Glu,Tyr) 4:l Store powder at -20 °C. Dissolve powder in phosphate buffered saline (PBS) for 50mg/ml solution. Store 1ml aliquots at -20 °C. When making plates dilute to 250 ⁇ g/ml in Gibco
  • Reaction Buffer lOOmM Hepes, 20mM MgCl 2 , 4mM MnCl 2 , 5mM DTT, 0.02%BSA,
  • Washing Buffer PBS with 0.1% Tween 20
  • TMB Substrate mix TMB substrate and Peroxide solutions 9:1 just before use or use K-Blue
  • Plate Preparation Dilute PGT stock (50mg/ml, frozen) in PBS to a 250 ⁇ g/ml. Add 125 ⁇ l per well of Corning modified flat bottom high affinity ELISA plates (Corning #25805-96). Add 125 ⁇ l PBS to blank wells. Cover with sealing tape and incubate overnight 37°C. Wash lx with 250 ⁇ l washing buffer and dry for about 2hrs in 37°C dry incubator. Store coated plates in sealed bag at 4°C until used.
  • the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4 mM MnCl 2 , 20 mM MgCl 2 , 5 mM DTT, 0.2% BSA, 200 mM NaVO 4 under the analogous assay conditions.
  • Compounds of formulas 1-109 may have therapeutic utility in the treatment of diseases involving both identified, including those not mentioned herein, and as yet unidentified protein tyrosine kinases which are inhibited by compounds of formulas 1-109.
  • the human recombinant enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using conventional methods.
  • a protocol that can be used is that provided with the purchased reagents with minor modifications.
  • the reaction is carried out in a buffer consisting of 50mM Tris pH 7.5, lOOmM NaCI, ImM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and lOmM MgCl 2 (commercial buffer) supplemented with fresh 300 ⁇ M ATP (31 ⁇ Ci/ml) and 30 ⁇ g/ml histone type IIIss final concentrations.
  • a reaction volume of 80 ⁇ L, containing units of enzyme is run for 20 minutes at 25 degrees C in the presence or absence of inhibitor.
  • the reaction is terminated by the addition of 120 ⁇ L of 10% acetic acid.
  • the substrate is separated from unincorporated label by spotting the mixture on phosphocellulose paper, followed by 3 washes of 5 minutes each with 75 ⁇ M phosphoric acid. Counts are measured by a betacounter in the presence of liquid scintillant.
  • the catalytic subunit of PKC may be obtained commercially (Calbiochem).
  • a radioactive kinase assay is employed following a published procedure (Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 3:166, 1220-1227 (1990)). Briefly, all reactions are performed in a kinase buffer consisting of 50 mM Tris-HCl pH7.5, lOmM MgCl 2 , 2mM DTT, ImM EGTA, 100 ⁇ M ATP, 8 ⁇ M peptide, 5% DMSO and 33 P ATP (8Ci/mM).
  • Erk2 enzyme source The recombinant murine enzyme and assay buffer may be obtained commercially
  • HUVEC cells from pooled donors can be purchased from Clonetics (San Diego, CA) and cultured according to the manufacturer directions. Only early passages (3-8) are used for this assay. Cells are cultured in 100 mm dishes (Falcon for tissue culture; Becton Dickinson; Madison, England) using complete EBM media (Clonetics).
  • cells are trypsinized and seeded at 0.5-1.0 x 10 5 cells/well in each well of 6-well cluster plates (Costar; Cambridge, MA). 3. 3-4 days after seeding, plates are typically 90-100% confluent. Medium is removed from all the wells, cells are rinsed with 5-10ml of PBS and incubated 18-24h with 5ml of EBM base media with no supplements added (i.e., serum starvation).
  • Orthovanadate (Sigma) and cells are lysed and scraped in 200 ⁇ l of RIP A buffer (50mM Tris- HCl) pH7, 150mMNaCl, 1% NP-40, 0.25% sodium deoxycholate, ImM EDTA) containing protease inhibitors (PMSF ImM, aprotinin 1 ⁇ g/ml, pepstatin 1 ⁇ g/ml, leupeptin 1 ⁇ g/ml, Na vanadate ImM, Na fluoride ImM) and 1 ⁇ g/ml of Dnase (all chemicals from Sigma Chemical Company, St Louis, MO). The lysate is spun at 14,000 rpm for 30min, to eliminate nuclei.
  • Equal amounts of proteins are then precipitated by addition of cold (-20 °C) Ethanol (2 volumes) for a minimum of 1 hour or a maximum of overnight.
  • Pellets are reconstituted in Laemli sample buffer containing 5% -mercaptoethanol (BioRad; Hercules, CA) and boiled for 5min.
  • the proteins are resolved by polyacrylamide gel electrophoresis (6%, 1.5mm Novex, San Deigo, CA) and transferred onto a nitrocellulose membrane using the Novex system.
  • the proteins After blocking with bovine serum albumin (3%), the proteins are probed overnight with anti-KDR polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or with anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid, NY) at 4 °C. After washing and incubating for 1 hour with HRP-conjugated F(ab) 2 of goat anti-rabbit or goat-anti-mouse IgG the bands are visualized using the emission chemiluminescience (ECL) system (Amersham Life Sciences, Arlington Heights, IL).
  • ECL emission chemiluminescience
  • This assay measures the capacity of compounds to inhibit the acute increase in uterine weight in mice which occurs in the first few hours following estrogen stimulation.
  • This early onset of uterine weight increase is known to be due to edema caused by increased permeability of uterine vasculature.
  • Cullinan-Bove and Koss (Endocrinology (1993), 133:829-837) demonstrated a close temporal relationship of estrogen-stimulated uterine edema with increased expression of VEGF mRNA in the uterus.
  • this system can serve as a model for in vivo inhibition of VEGF signalling and the associated hyperpermeability and edema.
  • Materials All hormones can be purchased from Sigma (St. Louis, MO) or Cal Biochem (La Jolla, CA) as lyophilized powders and prepared according to supplier instructions. Vehicle components (DMSO, Cremaphor EL) can be purchased from Sigma (St. Louis, MO). Mice (Balb/c, 8-12 weeks old) can be purchased from Taconic (Germantown, NY) and housed in a pathogen-free animal facility in accordance with institutional Animal Care and Use Committee Guidelines. Method:
  • mice are given an intraperitoneal (i.p.) injection of 12.5 units of pregnant mare's serum gonadotropin (PMSG).
  • PMSG pregnant mare's serum gonadotropin
  • Day 3 Mice receive 15 units of human chorionic gonadotropin (hCG) i.p.
  • mice are randomized and divided into groups of 5-10. Test compounds are administered by i.p., i.v. or p.o. routes depending on solubility and vehicle at doses ranging from 1-100 mg/kg. Vehicle control group receive vehicle only and two groups are left untreated. Thirty minutes later, experimental, vehicle and 1 of the untreated groups are given an i.p. injection of 17 -estradiol (500 mg/kg). After 2-3 hours, the animals are sacrificed by CO 2 inhalation. Following a midline incision, each uterus was isolated and removed by cutting just below the cervix and at the junctions of the uterus and oviducts.
  • Fat and connective tissue were removed with care not to disturb the integrity of the uterus prior to weighing (wet weight).
  • Uteri are blotted to remove fluid by pressing between two sheets of filter paper with a one liter glass bottle filled with water. Uteri are weighed following blotting (blotted weight). The difference between wet and blotted weights is taken as the fluid content of the uterus.
  • Mean fluid content of treated groups is compared to untreated or vehicle treated groups. Significance is determined by Student's test. Non-stimulated control group is used to monitor estradiol response.
  • Certain compounds of this invention which are inhibitors of angiogenic receptor tyrosine kinases can also be shown active in a Matrigel implant model of neovascularization.
  • the Matrigel neovascularization model involves the formation of new blood vessels within a clear marble of extracellular matrix implanted subcutaneously which is induced by the presence of proangiogenic factor producing tumor cells (for examples see: Passaniti, A., et al, Lab. Investig. (1992), 67(4), 519-528; Anat. Rec. (1997), 249(1), 63-73; Int. J. Cancer (1995), 63(5), 694-701; Vase. Biol. (1995), 15(11), 1857-6).
  • the model preferably runs over 3-4 days and endpoints include macroscopic visual/image scoring of neovascularization, microscopic microvessel density determinations, and hemoglobin quantitation (Drabkin method) following removal of the implant versus controls from animals untreated with inhibitors.
  • the model may alternatively employ bFGF or HGF as the stimulus.
  • the compounds of the present invention may be used in the treatment of protein kinase-mediated conditions, such as benign and neoplastic proliferative diseases and disorders of the immune system.
  • diseases include autoimmune diseases, such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis and systemic lupus erythematosus; psoriasis, organ transplant rejection (e.g,.
  • kidney rejection, graft versus host disease benign and neoplastic proliferative diseases
  • human cancers such as lung, breast, stomach, bladder, colon, pancreatic, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), glioblastoma, infantile hemangioma, and diseases involving inappropriate vascularization (for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings).
  • diseases vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings.
  • Such inhibitors may be useful in the treatment of disorders involving VEGF mediated edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury and adult respiratory distress syndrome (ARDS).
  • ARDS adult respiratory distress syndrome
  • the compounds of the invention may be useful in the treatment of pulmonary hypertension, particularly in patients with thromboembolic disease (J. Thorac. Cardiovasc. Surg. 2001, 122 (1), 65-73).
  • This invention is intended to encompass compounds having formula (I) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
  • Scheme 1 shows the synthesis of compounds of formula (4).
  • Compounds of formula (3) can be reacted with an appropriately substituted isocyanate (R ⁇ NCO) to provide compounds of formula (4).
  • R ⁇ NCO isocyanate
  • solvents used in these reactions include THF, dichloromethane, and MTBE.
  • the reaction is typically conducted at a temperature of about 0 °C to about 25 °C for about 1 hour to about 14 hours.
  • Compounds of formula (la) can be prepared following the procedures described in Scheme 2.
  • Compounds of formula (5) can be converted to compounds of formula (6) by treatment with hydrazine.
  • solvents include n-butanol, ethanol, n-pentanol, and n-hexanol. The reaction is typically conducted at about 80 °C to about 120 °C for about 2 to about 12 hours.
  • Compounds of formula (6) where R 9 is hydrogen can be converted to compounds of formula (6) where R 9 is alkenyl, alkoxyalkyl, alkyl, heterocyclylalkyl, hydroxyalkyl, or (NR a R b )alkyl by treatment with the appropriately substituted alkylating agent in the presence of a base under conditions known to those of ordinary skill in the art. Conversion of compounds of formula (6) to compounds of formula (la) can be accomplished by treatment with compounds of formula (7) in the presence of a palladium catalyst and a base.
  • Representative palladium catalysts include Pd(PPh 3 ) , Pd(o-tol 3 P) 2 Cl 2 , PdCi2(dppf), and PdCi 2 (dppf)-CH 2 Ci 2 .
  • bases include sodium carbonate, cesium carbonate, and potassium carbonate.
  • Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically conducted at temperatures between about 60 °C and about 130 °C (optionally in a microwave for about 5 to about 25 minutes) for about 4 to about 24 hours.
  • compounds of ormu a (8) can be converted to compounds of formula (9) by treatment with NBS in the presence of a radical initiator such as benzoyl peroxide AIBN.
  • a radical initiator such as benzoyl peroxide AIBN.
  • solvents used in this reaction include CC1 4 , benzene, and CHC1 3 .
  • the reaction is typically conducted at about 60 to about 80 °C for about 4 to about 48 hours.
  • Compounds of formula (9) can be converted to compounds of formula (5a) by treatment with a nucleophile (Z) (for example, an amine or an alcohol).
  • a nucleophile for example, an amine or an alcohol.
  • solvents used in these reactions include THF, DMF, NMP, and DME.
  • the reaction is typically conducted at about 20 °C to about 60 °C for about 12 to about 24 hours.
  • Scheme 4 shows the synthesis of compounds of formula (lb).
  • Compounds of formula (6) (prepared by the methods described in Scheme 2) can be converted to compounds of formula (10) by treatment with an appropriately substituted borane or other organometallic reagent such as a stannane or organozinc reagent in the presence of a palladium catalyst and optionally a base.
  • Representative palladium catalysts include Pd(PPh 3 ) , Pd(o-tol 3 P) 2 Cl 2 , PdCl 2 (dppf), and PdCl 2 (dppf)-CH 2 Cl2.
  • bases include sodium carbonate, cesium carbonate, and potassium carbonate.
  • Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically conducted at temperatures between about 60 °C and about 130 °C for about 4 to about 24 hours.
  • Compounds of formula (10) can be converted to compounds of formula (lb) by treatment with the appropriately substituted electrophile to generate L (i.e., an isocyanate of formula R ⁇ NCO).
  • L i.e., an isocyanate of formula R ⁇ NCO.
  • solvents include dichloromethane, chloroform, THF, DMF, and MTBE. The reaction is typically conducted at about -5 °C to about 25 °C for about 12 to about 24 hours.
  • compounds of formula (11) can be reacted with the compound of formula (12), a palladium catalyst, and potassium acetate, then treated with compounds of formula (6) in the presence of a palladium catalyst and a base to provide compounds of formula (lb).
  • Representative palladium catalysts include Pd(PPh 3 ) 4 , Pd(o- tol 3 P) 2 Cl 2 , PdCl 2 (dppf), and PdCl 2 (dppf)-CH 2 Cl 2 .
  • bases include sodium carbonate, cesium carbonate, and potassium carbonate.
  • Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically conducted at temperatures between about 60 °C and about 130 °C for about 4 to about 24 hours.
  • Compounds of formula (Id) can be prepared as described in Scheme 7.
  • Compounds of formula (16) can be converted to compounds of formula (17) using the conditions described in Schemes 2 and 4.
  • Compounds of fonnula (17) can be converted to compounds of formula (18) (where L 2 is an alkenyl group and R d is (NR a R b )carbonyl or alkoxycarbonyl) by treatment with a palladium catalyst and a base such as triethylamine or diisopropylethylamine.
  • solvents include THF and 1,4-dioxane.
  • the reaction is typically conducted at about 80 to about 150 °C for about 30 minutes to about 6 hours.
  • Scheme 8 shows the synthesis of compounds of formula (Ie).
  • Compounds of formula (21) (where Q is Br or I) can be reacted with the compound of formula (22) in the presence of potassium tert-butoxide to provide compounds of formula (23).
  • solvents used in this reaction include DMF, DME, and NMP. The reaction is typically conducted at about 20 °C to about 35 °C for about 15 minutes to about 12 hours.
  • Example IB N-(3-methylphenyl)-N'-r4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl1urea
  • a 0 °C mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (5.03g, 23 mmol) and l-isocyanato-3-methylbenzene (2.95 mL, 23 mmol) in THF (90 mL) was stirred at room temperature for 1 hour, concentrated, suspended in acetonitrile, and filtered. The filter cake was dried to provide 8.09g of the desired product.
  • Example IC N- f4-(3 -amino- 1 H-indazol-4-yl)phenyl1 -N'-(3 -methy lphenyl)urea
  • Example 1 A 60mg, 0.24 mmol
  • Example IB 103mg, 0.29 mmol
  • Na 2 CO 64mg, 0.6 mmol
  • DME 8 mL
  • water 2 mL
  • Pd(PPh 3 ) 14mg, 0.012 mmol
  • the combined extracts were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 5-8% methanol/dichloromethane to provide 56mg (66% yield) of the desired product.
  • Example 3 N- f4-(3 -amino- 1 H-indazol-4-yl)phenyll -N'-(3 -chlorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-chloro- 3-isocyanatobenzene for l-isocyanato-3-methylbenzene in Examples 1B-C and purifying the crude product by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min.
  • Example 4 N-r4-(3-amino-lH-indazol-4-yl)phenyll-N'-r3-(trifluoromethyl)phenyl1urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 1- isocyanato-3-(trifluoromethyl)benzene for l-isocyanato-3-methylbenzene in Examples 1B-C and purifying the product by preparative HPLC using the conditions described in Example 3.
  • Example 5A N-(2-fluoro-5-methylphenyl)-N'- f4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl ⁇ lurea
  • a 0 °C mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.5 g, 2.28 mmol) and l-fluoro-2-isocyanato-4-methylbenzene (0.297 mL, 2.28 mmol) in dichloromethane (15 mL) was allowed to gradually warm to room temperature and stirred overnight.
  • the resulting suspension was diluted with hexanes resulting in the formation of more precipitate, which was collected by filtration to provide 0.68g of the desired product.
  • MS (ESI(+)) m e 370.7 (M+H) + .
  • Example 5B N-r4-(3-amino-lH-i ⁇ dazol-4-yl)phenyll-N'-(2-fluoro-5-methylphenyl)urea
  • a mixture of Example 1 A (80mg, 0.32 mmol), Example 5A (144mg, 0.39 mmol) and Na 2 CO 3 (58mg) in DME (3 mL) and water (1 mL) was degassed with nitrogen for 2 minutes, treated with Pd(PPh 3 ) 4 (19 mg, 0.0161 mmol), and degassed with nitrogen for another 2 minutes.
  • the vial was capped and heated to 160 °C for 10 minutes with stirring in a Smith Synthesizer microwave oven (at 300W).
  • Example 7 N- r4-(3 -amino- 1 H-indazol-4-yl)phenyll -N'-(3 -bromophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-bromo- 3-isocyanatobenzene for l-isocyanato-3-methylbenzene in Examples 5A-B. !
  • Example 10 N- f4-(3 -amino- 1 H-indazol-4-yl)pheny 1] -N'-phenylurea
  • the desired product was prepared by substituting isocyanatobenzene for 1- isocyanato-3-methylbenzene in Examples 5A-B and purifying the crude product as described in Example IC.
  • Example 11 N- f4-(3 -amino- 1 H-indazol-4-yl)phenyll -N'-(3 -fluoro-4-methylphenyl)urea
  • the desired product was prepared by substituting 2-fluoro-4-isocyanato-l- methylbenzene for l-isocyanato-3-methylbenzene in in Examples 5A-B and purifying the crude product as described in Example IC.
  • N- f4-(3 -amino- 1 H-indazol-4-yl)phenyll -N'-(4-fluorophenyl)urea The desired product was prepared by substituting l-fluoro-4-isocyanatobenzene for 1- isocyanato-3-methylbenzene in in Examples 5A-B and purifying the crude product as described in Example IC.
  • the desired product was prepared by substituting l-fluoro-3-isocyanatobenzene for 1- isocyanato-3-methylbenzene in in Examples 5A-B and purifying the crude product as described in Example IC.
  • Example 15A A solution of Example 15A (19.3g, 69.1 mmol) in thionyl chloride (60 mL) was heated to 80 °C for 3 hours, cooled to room temperature, and concentrated. The residue was dissolved in THF (100 mL), cooled to 0 °C, treated with concentrated NH 4 OH (80 mL), stirred at room temperature for about 18 hours, and concentrated. The concentrate was suspended in water and filtered. The filter cake was washed with water and dried to provide 18.67g of the desired product. MS (CI NH 3 ) m/e 280 (M+H) + .
  • Example 15C 2-fluoro-6-iodo-3-methylbenzonitrile
  • a solution of Example 15B (18.6g, 66.7 mmol) in DMF (190 mL) was treated dropwise with thionyl chloride (24mL, 333 mmol), heated to 115 °C for 16 hours, cooled to room temperature, poured into ice, and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide 12.35g (71% yield) of the desired product. MS (CI NH3) m/e 279 (M+NH 4 ) + .
  • Example 15D 3-(bromomethyl)-2-fluoro-6-iodobenzonitrile
  • a mixture of Example 15C (8.0g, 30.6 mmol), NBS (6.54g, 36.78 mmol), and benzoyl peroxide (0.5g ) in CC1 (100 mL) was heated to reflux for 36 hours during which time additional NBS (9g) and benzoyl peroxide(1.5g) was added in 3 portions.
  • the suspension was filtered and the filtrate was concentrated.
  • the residue was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide 4.83g (46% yield) of the desired product.
  • Rf 0.27 (20% ethyl acetate/hexanes).
  • Example 15E 2-fluoro-6-iodo-3-(4-morpholinylmethyl)benzonitrile
  • a solution of Example 15D (710mg, 2.09 mmol) and morpholine (0.546 mL, 6.25 mmol) in DMF (8 mL) was stirred at room temperature overnight, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated to provide 0.7 lg of the desired product.
  • R f 0.4 (ethyl acetate).
  • Example 15F 4-iodo-7-(4-morpholinylmethyl)- 1 H-indazol-3 -amine
  • the desired product was prepared by substituting Example 15E for 2 ⁇ fluoro-6- iodobenzonitrile in Example IA.
  • R f 0.18 (ethyl acetate).
  • Example 15G 4-(4-aminophenyl)-7-(4-mo holinylmethyl)- 1 H-indazol-3 -amine
  • the desired product was prepared by substituting Example 15F and 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline for Example IA and IB, respectively, in
  • Example 15G N- ⁇ 4- ⁇ 3 -amino-7-(4-morpholinylmethyl)- 1 H-indazol-4-yllphenyl ) -N'-(3 -fluorophenyl)urea
  • dichloromethane 50mg, 0.155 mmol
  • l-fluoro-3-isocyanatobenzene 0.021 mL
  • the concentrate was purified by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide 24mg of the desired product as the trifluoroacetate salt.
  • Example 16 N- ⁇ 4- -amino-7-(4-morpholinylmethyl)- 1 H-indazol-4-yllphenyl ⁇ -N'-(3 -methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 1- isocyanato-3-methylbenzene for l-fluoro-3-isocyanatobenzene in Example 15H.
  • the vial was capped and heated to 140- 150 °C for 8-10 minutes with stirring in a Smith Synthesizer microwave oven (at 300W).
  • the reaction was poured into water and extracted three times with ethyl acetate.
  • the combined extracts were washed with water and brine, dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by HPLC using the conditions in Example 15H to provide 55mg of the desired product as the trifluoroacetate salt.
  • Example 20A 4-iodo-7-
  • the desired product was prepared by substituting 1-methylpiperazine for morpholine in Examples 15E-F.
  • Example 20B N-(4- ⁇ 3 -amino-7-
  • the desired product was prepared as the trifluoroacetate salt by substituting Example
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 20A andN-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-N'-[3- (trifluoromethyl)phenyl]urea, respectively, in Example 19.
  • Example 25 N-(4- ⁇ 3-amino-7-r(4-methyl-l-piperazinyl)methyll-lH-indazol-4-yl ⁇ phenyl)-N'-(2-fluoro-5- methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 20A andN-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19.
  • the desired product was prepared by substituting l,2-difluoro-4-iodobenzene for 2- fluoro-4-iodo-l-methylbenzene in Examples 15A-C.
  • Example 15H The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and l-bromo-3-isocyanatobenzene for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the trifluoroacetate salt by substituting Example 26B and l-chloro-3-isocyanatobenzene for Example 15G and l-fiuoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 29 N-r4-(3-amino-7-fluoro-lH-indazol-4-yl)phenyl1-N'-(3-methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 26B and l-isocyanato-3-methylbenzene for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 30 N- 4-(3-amino-7-fluoro-lH-indazol-4-yl)phenvn-N'-(3-cyanophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 26B and 3-isocyanatobenzonitrile for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 31 A and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)phenyl]urea for Example 15F and N-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea, respectively, in Example 19.
  • Example 34A 4-iodo- 1 -methyl- 1 H-indazol-3 -amine
  • the desired product was prepared by substituting N-methylhydrazine for hydrazine hydrate in Example 1 A.
  • Example 34B 4-(4-aminophenyl)- 1 -methyl- 1 H-indazol-3 -amine
  • the desired product was prepared by substituting Example 34A and 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline for Example IA and IB, respectively, in Example IC.
  • MS (ESI(+)) m/e 239 (M+H) + .
  • the desired product was prepared by substituting l-isocyanato-3-methylbenzene and Example 34B for l-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H.
  • the resulting product was purifed by flash column chromatography on silica gel with 5-8% methanol/dichloromethane to provide the desired product.
  • Example 37 N-f4-(3 -amino- 1 -methyl- 1 H-indazol-4-yl)phenyl1-N'-(4-methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 1 - isocyanato-4-methylbenzene and Example 34B for l-fluoro-3 -isocyanatobenzene and Example 15G, respectively, in Example 15H.
  • Example 38 N-f4-(3 -amino- 1 -methyl- lH-indazol-4-y l)pheny 11 -N'-(3-methoxyphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 1- isocyanato-3-methoxybenzene and Example 34B for l-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example 15H.
  • Example 39 N- r4-(3 -amino- 1 -methyl- 1 H-indazol-4-yl)phenyl1-N'-(3 -fluorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 34B for Example 15G in Example 15H.
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-chloro- 3 -isocyanatobenzene and Example 34B for l-fluoro-3 -isocyanatobenzene and Example 15G, respectively, in Example 15H.
  • Example 42 N 4-(3 -amino- 1 -methyl- 1 H-indazol-4-yl)phenyn-N'- ⁇ 3 -(trifluoromethyl)phenyllurea
  • the desired product was prepared as the trifluoroacetate salt by substituting 1- isocyanato-3-(trifluoromethyl)benzene and Example 34B for l-fluoro-3 -isocyanatobenzene and Example 15G, respectively, in Example 15H.
  • Example 44B N-r4-(3-amino-lH-indazol-4-yl)-2-fluorophenyll-N'-(3-methylphenyl)urea
  • a mixture of Example 44A (lOOmg, 0.31 mmol), bis(pinacolato)diboron (86mg, 0.33 mmol), Pd(dppf)Cl 2 (lOmg) and potassium acetate (270mg) in DMF (3 mL) was heated to 80 °C for 2 hours, treated with Example 1 A (64mg, 0.24 mmol), Pd(d ⁇ f)Cl 2 (6mg), Na 2 CO 3 (78mg), and water (lmL), heated to 80 °C for 18 hours, cooled to room temperature, and concentrated.
  • Example 45 N- f4-(3 -amino- 1 H-indazol-4-y [ ⁇ -fluorophenyl] -N'-(3 -fluorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro- 3-isocyanatobenzene for l-isocyanato-3 -methy Ibenzene in Examples 44 A-B.
  • Example 46 N-r4-(3-amino-lH-indazol-4-yl)-2-fluorophenyl]-N'-(3,5-dimethylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 1- isocyanato-3,5-dimethy Ibenzene for l-isocyanato-3 -methylbenzene in Examples 44 A-B.
  • Example 48 N- f4-(3 -amino- 1 H-indazol-4-yl)-2-fluorophenyll-N'-(3 -chloro-4-fluorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 2-chloro- l-fluoro-4-isocyanatobenzene for l-isocyanato-3-methylbenzene in Examples 44A-B.
  • Example 49 N-r4-(3-amino-lH-indazol-4-yl)-2-fluorophenyll-N'-(3-fluoro-4-methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 2-fluoro- 4-isocyanato-l -methylbenzene for l-isocyanato-3 -methylbenzene in Examples 44 A-B.
  • Example 50 N- f4-(3 -amino- 1 H-indazol-4-yl)-2-fluoropheny 11 -N'-(3 -chlorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 1-chloro- 3 -isocyanatobenzene for l-isocyanato-3 -methylbenzene in Examples 44A-B.
  • Example 52 N- ⁇ 4- -amino- 1 -(2-hydroxyethyl)- 1 H-indazol-4-yllphenyl) -N'-(3 -methylphenyl)urea
  • the desired product was prepared by substituting 2-hydrazinoethanol for hydrazine hydrate in Examples 1 A-C.
  • Example 53A methyl T4-(3 -amino- 1 H-indazol-4-yl)phenyll acetate
  • the desired product was prepared by substituting methyl (4-bromophenyl)acetate and K PO 4 for Example 44 A and Na 2 CO 3 , respectively, in Example 44B. Additionally the reaction was carried our under anhydrous conditions. MS (ESI(+)) m/e 304 (M+H) + .
  • Example 53B f4-(3 -amino- 1 H-indazol-4-yl)phenyll acetic acid
  • a solution of Example 53A (140mg) in 1:1 methanol/10% NaOH (1 mL) was stirred at room temperature for 2 hours and adjusted to pH 3 with 10% HC1.
  • the resulting precipitate was collected by filtration to provide 108mg of the desired product.
  • Example 53C 2- f4-(3 -amino- 1 H-indazol-4-yl)phenyll -N-phenylacetamide A mixture of Example 53B (40mg, 015mmol), diisopropylethylamine (0.078 mL,
  • Example 54 2- [4-(3 -amino- 1 H-indazol-4-yl)phenyll-N-(3 -chlorophenyl)acetamide
  • the desired product was prepared as the trifluoroacetate salt by substituting 3- chloroaniline for aniline in Example 53C.
  • Example 55 2-r4-(3-amino-lH-indazol-4-yl)phenyl1-N-(4-fluoro-3-methylphenyl)acetamide
  • the desired product was prepared as the trifluoroacetate salt by substituting 4-fluoro- 3-methylaniline for aniline in Example 53C.
  • the desired product was prepared by substituting 3-(trifluoromethyl)aniline for aniline in Example 53C, then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 57 2- r4-(3 -amino- 1 H-indazol-4-yl)phenyl]-N-(3 -methylphenyl)acetamide
  • the desired product was prepared as the trifluoroacetate salt by substituting 3- methylaniline for aniline in Example 53C.
  • Example 58 A 2-fluoro-6-iodo-3-methoxybenzonitrile The desired product was prepared by substituting 2-fluoro-4-iodo-l-methoxybenzene for 2-fluoro-4-iodo-l -methylbenzene in Examples 15A-C.
  • Example 60 N- f4-(3 -amino-7-methoxy- 1 H-indazol-4-y l)phenyll -N'-phenylurea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 58B and isocyanatobenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 61 N- F4-(3 -amino-7-methoxy- 1 H-indazol-4-yl)phenyll-N'-(3 -bromophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example
  • Example 62 N- ⁇ 4-(3 -amino-7-methoxy- 1 H-indazol-4-yl)phenyll-N'-(3 -ethylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 58B and l-isocyanato-3 -ethy Ibenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 63 N-r4-(3-amino-7-methoxy-lH-indazol-4-yl)phenyll-N'-(3-fluoro-4-methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 2-fluoro-4-isocyanato-l -methylbenzene for Example 15G and l-fluoro-3- isocyanatobenzene, respectively, in Example 15H.
  • Example 64 N- f4-(3 -amino-7-methoxy- 1 H-indazol-4-yl)pheny 11 -N'- r4-fluoro-3 - (trifluoromethyl)phenyllurea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 58B and l-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and l-fluoro-3- isocyanatobenzene, respectively, in Example 15H.
  • Example 65 N-r4-(3-amino-7-methoxy-lH-indazol-4-yl)phenyl1-N'-(3-chlorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 58B and l-chloro-3 -isocyanatobenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 68A 2-fluoro-3-hydroxy-6-iodobenzonitrile
  • dichloromethane 5 mL
  • BBr 3 2.5 mL, IM in dichloromethane, 2.5 mmol
  • the extract was dried (MgSO 4 ), filtered, and concentrated.
  • MS (ESI(-)) m/e 262 (M-H)-.
  • Example 68B 2-fluoro-6-iodo-3-(2-methoxyethoxy)benzonitrile
  • a mixture of Example 68A (104mg, 0.39 mmol), l-bromo-2-methoxyethane (0.088 mL) and K 2 CO 3 (163mg) in acetone (3 mL) was heated to 60 °C for 18 hours, cooled to room temperature, and partitioned between diethyl ether and water. The extract was dried
  • the desired product was prepared by substituting Example 68C and l-isocyanato-3 - methylbenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15, then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 69 N- ⁇ 4- ⁇ 3 -amino-7-(2-methoxyethoxy)- 1 H-indazol-4-y llphenyl ⁇ -N'-phenylurea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 68C and isocyanatobenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 15H The desired product was prepared as the trifluoroacetate salt by substituting Example 68C and l-bromo-3-isocyanatobenzene for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 72 N- ⁇ 4- f3 -amino-7-(2-methoxyethoxy)- 1 H-indazol-4-ynphenyl ⁇ -N'-(3-chlorophenyl)urea
  • the desired product was prepared by as the trifluoroacetate salt substituting Example 68C and l-chloro-3 -isocyanatobenzene for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 75 N-(4- ⁇ 3-amino-7-r2-(4-mor ⁇ holinyl)ethoxyl-lH-indazol-4-yl ⁇ henyl)-N'-(3- methylphenyl)urea
  • Example 75A 2-fluoro-6-iodo-3-r2-(4-morpholinyl)ethoxylbenzonitrile
  • a mixture of Example 68 A (250mg, 0.95 mmol), 2-(4-morpholinyl)ethanol (0.19 mL) and triphenylphosphine on resin (630mg, 3mmol/g, 1.9 mmol) in THF (5 mL) was treated with DEAD (0.179 mL) and stirred at room temperature for about 18 hours.
  • Example 75B 4-(4-aminophenyl)-7-r2-(4-morpholinyl)ethoxyl-lH-indazol-3-amine The desired product was prepared by substituting Example 75 A for Example 15E in Examples 15F-G. MS (ESI(+)) m/e 354 (M+H) + .
  • Example 75C N-(4- ⁇ 3-amino-7-r2-(4-morpholinyl)ethoxyl-lH-indazol-4-yl ⁇ phenyl)-N'-(3- methylphenyl)urea
  • the desired product was prepared by substituting Example 75B and l-isocyanato-3 - methylbenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 77 N-(4- ⁇ 3-amino-7-r2-(4-morpholinyl)ethoxyl-lH-indazol-4-yl ⁇ phenyl)-N'-(3- fluorophenyPurea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B for Example 15G in Example 15H.
  • Example 78 N-(4- ⁇ 3-amino-7-r2-(4-morpholinyl)ethoxyl-lH-indazol-4-yl ⁇ phenyl)-N'-(3- bromophenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and l-bromo-3 -isocyanatobenzene for Example 15G and l-fluoro-3- isocyanatobenzene, respectively, in Example 15H.
  • Example 82 N-(4- ⁇ 3-amino-7-r2-(4-morpholinyl)ethoxyl-lH-indazol-4-yl>phenyl)-N'-(3- chlorophenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 75B and l-chloro-3 -isocyanatobenzene for Example 15G and l-fluoro-3- isocyanatobenzene, respectively, in Example 15H.
  • MS (ESI(+)) m/e 507 (M+H) + ; !
  • the desired product was prepared by substituting 4-bromo-2-fluoro-6- iodobenzonitrile for 2-fluoro-6-iodobenzor ⁇ itrile in Example 1 A.
  • Example 84A The desired product was prepared by substituting Example 84A and 4- nitrophenylboronic acid for Example IA and Example IB, respectively, in Example IC.
  • Example 84D (2E)-3-r3-amino-4-(4-aminophenyl)-lH-indazol-7-yn-N,N-dimethylacrylamide
  • a solution of Example 84C (113mg, 0.32 mmol) in a mixture of ethanol (1 mL), methanol (1 mL), and THF (1 mL) was treated with iron powder (144mg) and NH 4 C1 (17mg), heated to 85 °C for 4 hours, cooled to room temperature, and filtered. The filtrate was partitioned between water and ethyl acetate and the organic phase was dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 75mg of the desired product. MS (ESI(+)) m/e 322 (M+H) + .
  • Example 15H N,N-dimethylacrylamide
  • Example 84D l-chloro-3- isocyanatobenzene
  • Example 15G l-fluoro-3-isocyanatobenzene
  • Example 15H purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 86 (2E)-3 -(3 -amino-4- ⁇ 4- 1 ⁇ ( ⁇ T3 -(trifluoromethyl)phenyll amino ⁇ carbonyl)aminolphenyl ⁇ - 1 H- indazol-7-yl)-N,N-dimethylacrylamide
  • the desired product was prepared by substituting Example 84D and l-isocyanato-3 - (trifluromethyl)benzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example 87A 4-(4-aminophenyl)-7- r2-(dimethylamino)ethoxy1- 1 H-indazol-3 -amine
  • the desired product was prepared by substituting 2-(dimethylamino)ethanol for 2-(4- morpholinyl)ethanol in Example 75A-B.
  • MS (ESI(+)) m/e 312 (M+H) + .
  • Example 87B N-(4- ⁇ 3-amino-7-r2-(dimethylamino)ethoxy1-lH-indazol-4-yl ⁇ phenyl)-N'-phenylurea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting
  • Example 89 N-(4- ⁇ 3-amino-7-r2-(dimethylamino)ethoxyl-lH-indazol-4-yl ⁇ henyl)-N'-(3- methylphenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 87A and l-isocyanato-3 -methylbenzene for Example 15G and l-fluoro-3- isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared by substituting l-(2-hydroxyethyl)-2-pyrrolidinone for 2-(4-morpholinyl)ethanol in Example 75A-B. MS (ESI(+)) m/e 352 (M+H) + .
  • Example 9 IB N-(4- ⁇ 3-amino-7-r2-(2-oxo-l-pyrrolidinyl)ethoxyl-lH-indazol-4-yl)phenyl)-N'-(3- methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 91A and l-isocyanato-3 -methylbenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 92 2- f4-(3 -amino- 1 -methyl- 1 H-indazol-4-yl)phenyll -N-(3 -methy lphenyl)acetamide
  • the desired product was prepared by substituting Example 34A and 2-[4-(4,4,5,5- tetramethyl-[l,3,21dioxaborolan-2-yl)-phenyl]-N-m-tolyl-acetamide for Example IA and Example IB, respectively, in Example 53 C.
  • the crude product was purified by preparative HPLC using the conditions described in Example 3 to provide the desired product as the trifluoroacetate salt.
  • Example 93 N- f4-(3 -amino- 1 H-indazol-4-yl)-2-methylphenyll -N'-(3 -methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting 4-bromo- 2-methylaniline for 4-bromo-2-fluoroaniline in Example 44 A-B.
  • Example 94 N-(4- ⁇ 3-amino-7-r2-(2-oxo-l-pyrrolidinyl)ethoxy1-lH-indazol-4-yl)phenyl)-N'-(3- chlorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 91 A and l-chloro-3 -isocyanatobenzene for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • Example 95 A was prepared by substituting Example 95 A for Example 1 A in Example IC.
  • the desired product was prepared by substituting l-isocyanato-2- (trifluoromethyl)benzene for l-isocyanato-3-methylbenzene in Example IB.
  • Example 96B N- f4-(3 -amino- 1 ,2-benzisoxazol-4-yl)phenyll -N'- r2-(trifluoromethyl)phenynurea
  • the desired product was prepared by substituting Example 95A and Example 96A for Example 1 A and Example IB, respectively, in Example IC.
  • Example 97 N-r4-(3-amino-l,2-benzisoxazol-4-yl)phenyll-N'-(2-fluoro-5-methylphenyl)urea
  • the desired product was prepared by substituting Example 95 A and Example 5A for Example 1 A and Example IB, respectively, in Example 1 C.
  • the desired product was prepared by substituting l-isocyanato-3 - (trifluoromethyl)benzene for l-isocyanato-3 -methylbenzene in Example IB.
  • Example 95A and Example 98A were prepared by substituting Example 95A and Example 98A for Example IA and Example IB, respectively, in Example IC.
  • Example 99A N-r2-fluoro-5-(trifluoromethyl)phenyll-N'-r4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyllurea
  • the desired product was prepared by substituting l-fluoro-2-isocyanato-4- (trifluoromethyl)benzene for l-isocyanato-3 -methylbenzene in Example IB.
  • Example 99B N-r4-(3-amino-l,2-benzisoxazol-4-yl)phenyll-N'-r2-fluoro-5-(trifluoromethyl)phenyllurea
  • the desired product was prepared by substituting Example 95A and Example 99A for Example 1 A and Example IB, respectively, in Example IC.
  • Example 100A 2-fluoro-6-iodo-3-methoxybenzonitrile
  • the desired product was prepared by substituting 2-fluoro-4-iodo-l-methoxybenzene for 2-fluoro-4-iodo- 1 -methylbenzene in Examples 15 A-C.
  • Example 100B 4-iodo-7-methoxy- 1 ,2-benzisoxazol-3 -amine The desired product was prepared by substituting Example 100A for 2-bromo-6- fluorobenzonitrile in Example 95 A.
  • Example 100C 4-(4-aminophenyl)-7-methoxy- 1 ,2-benzisoxazol-3 -amine
  • the desired product was prepared by substituting Example 100B for Example 15F in Example 15G.
  • Example 100D N-r4-(3-amino-7-methoxy-l,2-benzisoxazol-4-yl)phenyl1-N'-r2-fluoro-5- (trifluoromethyl)phenyllurea
  • the desired product was prepared by substituting Example 100C and l-fluoro-2- isocyanato-4-(trifluoromethyl)benzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 101 N-r4-(3-amino-7-methoxy-l,2-benzisoxazol-4-yl)phenyll-N'-(3-methylphenyl)urea
  • the desired product was prepared by substituting Example 100C and l-isocyanato-3- methy Ibenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 102 N-r4-(3-amino-7-methoxy-l,2-benzisoxazol-4-yl)phenyll-N'-r3-(trifluoromethyl)phenyllurea
  • the desired product was prepared by substituting Example 100C and l-isocyanato-3 - (trifluoromethyl)benzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 103 N-r4-(3-amino-7-methoxy-l,2-benzisoxazol-4-yl)phenyll-N'-(3-chlorophenyl)urea
  • the desired product was prepared by substituting Example 100C and l-chloro-3- isocyanatobenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. !
  • Example 104 N- f4-(3 -amino-7-methoxy- 1 ,2-benzisoxazol-4-yl)phenyll -N'-(2-fluoro-5 -methylphenyl)urea
  • the desired product was prepared by substituting Example 100C and l-fluoro-2- isocyanato-4-methylbenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product. !
  • Example 105 A 4-iodo-7-(4-mo ⁇ holinylmethyl)- 1 ,2-benzisoxazol-3 -amine The desired product was prepared by substituting Example 15E for 2-bromo-6- fluorobenzonitrile in Example 95A.
  • Example 105B 4-(4-aminophenyl)-7-(4-morpholinylmethyl)- 1 ,2-benzisoxazol-3 -amine
  • the desired product was prepared by subsituting Example 105 A for Example 15F in Example 15G.
  • Example 107 N- ⁇ 4-r3-amino-7-(4-morpholinylmethyl)-l,2-benzisoxazol-4-yllphenyl ⁇ -N'-(3- chlorophenyl)urea
  • the desired product was prepared by substituting Example 105B and l-chloro-3- isocyanatobenzene for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • the desired product was prepared by substituting Example 105B and l-isocyanato-3 - methy Ibenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 109 N- ⁇ 4-r3-amino-7-(4-morpholinylmethyl)-l,2-benzisoxazol-4-yllphenyl ⁇ -N'-(2-fluoro-5- methylphenyl)urea
  • the desired product was prepared by substituting Example 105B and l-fluoro-2- isocyanato-4-methy Ibenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 105B and 1-isocyanato- 3,5-dimethylbenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 105B and l-isocyanato-3- phenoxybenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 112 N- ⁇ 4- ⁇ 3 -amino-7-(4-morpholinylmethyl)- 1 ,2-benzisoxazol-4-y llphenyl) -N'-(3 - bromophenyl)urea
  • the desired product was prepared by substituting Example 105B and l-bromo-3- isocyanatobenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 113A 4-iodo-7-r2-(4-morpholinyl)ethoxyl-l,2-benzisoxazol-3-amine
  • the desired product was prepared by substituting Example 75A for 2-bromo-6- fluorobenzonitrile in Example 95 A.
  • Example 113B 4-(4-aminophenyl)-7-r2-(4-morpholinyl)ethoxyl-l,2-benzisoxazol-3-amine The desired product was prepared by substituting Example 113A for Example 15F in Example 15G.
  • Example 114 N-(4- ⁇ 3-amino-7-r2-(4-morpholinyl)ethoxyl-l,2-benzisoxazol-4-yl ⁇ phenyl)-N'-(2-fluoro-5- methylphenyl)urea
  • the desired product was prepared by substituting Example 113B and l-fluoro-2- isocyanato-4-methylbenzene for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 116 N-(4- ⁇ 3-amino-7-r2-(4-morpholinyl)ethoxyl-l,2-benzisoxazol-4-y phenyl)-N'-(3- methylphenyl)urea
  • the desired product was prepared by substituting Example 113B and l-isocyanato-3 - methylbenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 15H The desired product was prepared by substituting Example 68C and l-fluoro-2- isocyanato-4-methylbenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the crude suspension was filtered and the solid collected was washed with dichloromethane to provide the desired product.
  • Example 119A 2-fluoro-6-iodo-3-(methoxymethoxy)benzonitrile
  • Example 119B N- ⁇ 4- ⁇ 3 -amino-7-(methoxymethoxy)- 1 H-indazol-4-yllphenyl ⁇ -N'-(2-fluoro-5- methylphenyl)urea
  • the desired product was prepared by substituting Example 119A and l-fluoro-2- isocyanato-4-methy Ibenzene for 2-fluoro-6-iodobenzonitrile and l-isocyanato-3 - methylbenzene, respectively, in Examples 1 A-IC.
  • Example 120 N-r4-(3-amino-7-hydroxy-lH-indazol-4-yl)phenyl1-N'-(2-fluoro-5-methylphenyl)urea
  • a mixture of Example 119B (90mg) and a 1 : 1 : 1 mixture of 3N HCl/methanol/THF (3 mL) was heated to 50 °C for 3 hours, concentrated to half its original volume, and partitioned between saturated NaHCO 3 and ethyl acetate. The organic extract was dried (MgSO 4 ), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 30mg of the desired product.
  • Example 121 A was prepared by substituting Example 15G in Example 15H.
  • Example 12 IB for Example 119B in Example 120, then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 122 N- f4-(3 -amino-7-hydroxy- 1 H-indazol-4-yl)phenyll -N'-(3 -bromophenyl)urea
  • Example 122 A N- ⁇ 4- [3 -amino-7-(methoxymethoxy)- 1 H-indazol-4-y llphenyl ⁇ -N'-(3 -bromophenyl)urea
  • the desired product was prepared by substituting Example 121 A and l-bromo-3- isocyanatobenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 122B N- f4-(3 -amino-7-hydroxy- 1 H-indazol-4-yl)phenyll-N'-(3 -bromophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example
  • Example 122 A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 123B N-r4-(3-amino-7-hydroxy-lH-indazol-4-yl)phenyll-N'-(3-ethylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 123 A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 124B N- f4-(3 -amino-7-hy droxy- 1 H-indazol-4-yl)phenyll -N'- r2-fluoro-5 - (trifluoromethyl)phenyllurea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example
  • Example 124A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 125B N- f4-(3 -amino-7-hy droxy- 1 H-indazol-4-yl)pheny 11 -N'- r4-fluoro-3 - (trifluoromethyl)phenyllurea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 125 A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 126 A N- ⁇ 4- -amino-7-(methoxymethoxy)- 1 H-indazol-4-yllphenyl) -N'-(3-chlorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 121A and l-chloro-3-isocyanatobenzene for Example 15G and l-fluoro-3- isocyanatobenzene, respectively, in Example 15H.
  • Example 126B N- f4-(3 -amino-7-hydroxy- 1 H-indazol-4-yl)phenyl1 -N'-(3 -chlorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example
  • Example 126 A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 127B N- f4-(3 -amino-7-hy droxy- 1 H-indazol-4-yl)phenyll -N'- ⁇ 3 -(trifluoromethy Dphenyllurea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 127 A for Example 119B in Example 120 then purifying the resulting product by HPLC using the conditions described in Example 15H.
  • Example 128 A N- ⁇ 4- ⁇ 3 -amino-7-(methoxymethoxy)- 1 H-indazol-4-yllphenyl ) -N'-phenylurea
  • Example 15H The desired product was prepared by substituting Example 121 A and isocyanatobenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 128 A N- f4-(3 -amino-7-hy droxy- 1 H-indazol-4-yl)phenyll -N'-phenylurea
  • the desired product can be prepared by substituting Example 128 A for Example 119B in Example 120.
  • Example 129B N-(4- ⁇ 3-amino-7-r2-(l-pyrrolidinyl)ethoxyl-lH-indazol-4-yl)phenyl)-N'-phenylurea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129 A and isocyanatobenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 130 N-(4- ⁇ 3 -amino-7- ⁇ 2-( 1 -pyrrolidiny l)ethoxyl - 1 H-indazol-4-yl ) phenyl)-N'-(3 - fluorophenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A for Example 15G in Example 15H.
  • Example 131 N-(4- ⁇ 3 -amino-7- ⁇ 2-( 1 -pyrrolidinyl)ethoxy1- 1 H-indazol-4-yl)phenyl)-N'-(2-fluoro-5- methylphenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and l-fluoro-2-isocyanato-4-methylbenzene for Example 15G and l-fluoro-3- isocyanatobenzene, respectively, in Example 15H.
  • Example 132 N-(4-(3-amino-7-r2-(l-pyrrolidinyl)ethoxyl-lH-indazol-4-yl) ⁇ henyl)-N'-(3- methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 129A and l-isocyanato-3 -methylbenzene for Example 15G and l-fluoro-3- isocyanatobenzene, respectively, in Example 15H.
  • Example 133 N-(4- ⁇ 3-amino-7-r2-(l-pyrrolidinyl)ethoxyl-lH-indazol-4-yl)phenyl)-N'-(3- bromophenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129A and l-bromo-3-isocyanatobenzene for Example 15G and l-fluoro-3- isocyanatobenzene, respectively, in Example 15H.
  • Example 135 N-(4- ⁇ 3-amino-7-r2-(l-pyrrolidinyl)ethoxy1-lH-indazol-4-yl)phenyl)-N'-(3- chlorophenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 129 A and l-chloro-3 -isocyanatobenzene for Example 15G and l-fluoro-3 - isocyanatobenzene, respectively, in Example 15H.
  • Example 137 A 4-(4-aminophenyl)-7- r2-(diethylamino)ethoxyl - 1 H-indazol-3 -amine The desired product was prepared by substituting 2-(diethylamino)ethanol for 2-(4- morpholinyl)ethanol in Examples 75A and 75B. MS (ESI(+)) m/e 340 (M+H) + .
  • Example 137B N-(4- ⁇ 3-amino-7-r2-(diethylamino)ethoxyl-lH-indazol-4-yl ⁇ phenyl)-N'-phenylurea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting
  • Example 138 N-(4- ⁇ 3-amino-7-r2-(diethylamino)ethoxyl-lH-indazol-4-yl)phenyl)-N'-(3- fluorophenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate salt) by substituting Example 137A for Example 15G in Example 15H.
  • Example 139 N-(4- ⁇ 3-amino-7-r2-(diethylamino)ethoxyl-lH-indazol-4-yl)phenyl)-N'-(2-fluoro-5- methylphenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate salt) by substituting Example 137A and l-fluoro-2-isocyanato-4-methy Ibenzene for Example 15G and l-fluoro-3 - isocyanatobenzene, respectively, in Example 15H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 137A and l-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 143 N-(4- ⁇ 3-amino-7- r2-(diethylamino)ethoxyl- 1 H-indazol-4-yl)phenyl)-N'-(3 - chlorophenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 137A and l-chloro-3 -isocyanatobenzene for Example 15G and l-fluoro-3 - isocyanatobenzene, respectively, in Example 15H.
  • Example 145 A 3 -(2- ⁇ P -amino-4-(4-aminophenyl)- 1 H-indazol-7-y lloxy ) ethyl)- 1,5,5 -trimethy 1-2,4- imidazolidinedione
  • the desired product was prepared by substituting 3-(2-hydroxyethyl)-l,5,5-trimethyl- 2,4-imidazolidinedione for 2-(4-morpholinyl)ethanol in Examples 75 A and 75B. !
  • Example 146 N-(4- ⁇ 3-amino-7-r2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethoxyl-lH-indazol-4- yl)phenyl)-N'-(3-chlorophenyl)urea
  • the desired product was prepared by substituting Example 145 A and l-chloro-3- isocyanatobenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 147 N-(4- ⁇ 3-amino-7-r2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethoxy1-lH-indazol-4- yl ) phenyl)-N'-(2-fluoro-5 -methy lphenyl)urea
  • the desired product was prepared by substituting Example 145 A and l-fluoro-2- isocyanato-4-methylbenzene for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane. !
  • Example 148 N-(4- ⁇ 3-amino-7-r2-(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)ethoxyl-lH-indazol-4- yl)phenyl)-N'-P-(ttifluoromethyl)phenyllurea
  • the desired product was prepared by substituting Example 145A and l-isocyanato-3- (trifluoromethyl)benzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 149A N-(4-bromo-2-ethylphenyl)-N'-(2-fluoro-5-methylphenyl)urea
  • a solution of 4-bromo-2-ethylaniline (200mg) in dichloromethane (10 mL) was treated with l-fluoro-2-isocyanato-4-methylbenzene (151mg), stirred at room temperature overnight, diluted with hexanes, and filtered. The filter cake provided 227mg of the desired product.
  • MS (ESI(+)) m/e 351,353 (M+H) + .
  • Example 149C N-r4-(3-amino-lH-indazol-4-yl)-2-ethylphenyll-N'-(2-fluoro-5-methylphenyl)urea
  • the desired product was prepared by substituting Example 149B and
  • Example 150 N- f4-(3 -amino- 1 H-indazol-4-yl)-2-ethylphenyll -N'- P -(trifluoromethyl)phenyllurea
  • the desired product was prepared by substituting l-isocyanato-3 -
  • Example 151 N-r4-(3-amino-7-fluoro-lH-indazol-4-yl)phenyll-N'-(2-fluoro-5-methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 26B and l-fluoro-2-isocyanato-4-methylbenzene for Example 15G and l-fluoro-3 - isocyanatobenzene, respectively, in Example 15H.
  • Example 26A A -78 °C solution of Example 26A (5.0g, 18.9 mmol) in THF was treated with LDA (2M in hexanes, 11.5 mL, 22.6 mmol), stirred for 1 hour at -78 °C, treated with methyl formate (2.34 mL, 37.8 mmol), stirred at -78 °C for 30 minutes, warmed to 0 °C for 1 hour, quenched with saturated NH 4 C1 and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO 4 ), filtered, and concentrated.
  • Example 152C N- ⁇ 4-r3-amino-7-fluoro-6-(hydroxymethyl)-lH-indazol-4-yllphenyl)-N'-(2-fluoro-5- methylphenyl)urea
  • Example 152B 50mg, 0.16 mmol
  • Example 5 A 66mg, 0.18 mmol
  • Pd(PPh 3 ) 4 9mg, 0.008 mmol
  • Na 2 CO 3 43mg, 0.4 mmol
  • the samples were cooled using 40 psi pressurized air.
  • the mixture was concentrated and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40mL/min to provide 26mg of the desired product as the trifluoroacetate salt.
  • Example 154 N- ⁇ 4- 3-amino-7-fluoro-6-(hydroxymethyl)-lH-indazol-4-yl1phenyl)-N'-(3- chlorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting N-(3- chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyljurea for Example 5A in Example 152C.
  • Example 155 N- ⁇ 4-r3-amino-7-fluoro-6-(hydroxymethyl)-lH-indazol-4-yllphenyl)-N'-(3- methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example IB for Example 5A in Example 152C.
  • Example 156 N- ⁇ 4-P-amino-7-fluoro-6-(hydroxymethyl)-lH-indazol-4-yllphenyl)-N'-(3- fluorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting N-(3- fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 152C.
  • Example 157C N-(4- ⁇ 3 -amino-6- r(diethylamino)methyll -7-fluoro- 1 H-indazol-4-yl ) phenyl)-N'-(2-fluoro-5 - methylphenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 157B for Example 152B in Example 152C.
  • Example 159 N-(4- ⁇ 3-amino-6-r(diethylamino)methyll-7-fluoro-lH-indazol-4-yl)phenyl)-N'-(3- chlorophenyl)urea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 157B and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]urea for Example 152B and Example 5 A, respectively, in Example 152C. !
  • Example 160 N-(4- ⁇ 3 -amino-6- r(diethylamino)methyll -7-fluoro- 1 H-indazol-4-yl) phenyl)-N'-(3 - methyrphenypurea
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 157B and Example IB for Example 152B and Example 5A, respectively, in Example 152C.
  • Example 161 A 4-iodo-7- ⁇ (3 -pyridinyloxy)methyl1 - 1 H-indazol-3 -amine The desired product was prepared by substituting 3-pyridinol for morpholine in
  • Example 161 A and Example 98 A for Example 152B and Example 5 A, respectively, in Example 152C then purifying the resulting producty by flash column chromatography on silica gel with 5-8% methanol/dichloromethane.
  • Example IA A mixture of Example IA (1.09g) and phthalic anhydride (0.75g) in dioxane (15 mL) was stirred overnight at 120 °C and concentrated. The residue was triturated from diethyl ether (15 mL) to provide 0.51g of the desired product. MS (ESI(+)) m/e 388 (M+H) + .
  • Example 162C 4-iodo- 1 - r2-(4-morpholinyl)ethyl1 - 1 H-indazol-3 -amine
  • a mixture of hydrazine hydrate (0.058 mL) and Example 162B (120mg, 0.24 mmol) in ethanol (5mL) was stirred at 0 °C for 3 hours and concentrated.
  • the residue was purified by flash column chromatography on silica gel with 5-8% methanol/dichloromethane to provide 95mg of the desired product.
  • Example 163 N-(4- ⁇ 3-amino-l-r2-(4-morpholinyl)ethyl1-lH-indazol-4-yl)phenyl)-N'-(3-fluorophenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting 162C for Example 15F in Examples 15G-H.
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 162C and l-chloro-3 -isocyanatobenzene for Example 15F and l-fluoro-3- isocyanatobenzene, respectively, in Examples 15G-H.
  • Example 166 N-(4- ⁇ 3-amino-l-r2-(4-morpholinyl)ethyll-lH-indazol-4-yl) ⁇ henyl)-N'-(3- methylphenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 162C and l-isocyanato-3 -methylbenzene for Example 15F and l-fluoro-3- isocyanatobenzene, respectively, in Examples 15G-H.
  • Example 167-1 and 167-11 N- f4-(3 -amino-6-bromo- 1 H-indazol-4-yl)pheny 11 -N'-(3 -methy lphenyl)urea and N-r4-(3-amino-4-bromo-lH-indazol-6-yl)phenyll-N'-(3-methylphenyl)urea
  • the desired product was prepared by substituting 2,4-dibromo-6-fluorobenzoic acid (prepared as described in Tetrahedron Lett. 1996, 37, 6551-6554) for Example 15A in Examples 15B and 15C.
  • Example 167A 4,6-dibromo- 1 H-indazol-3 -amine
  • the desired product was prepared by substituting Example 167A for 2-fluoro-6- iodobenzonitrile in Example IA.
  • Example 167-1 and 167-11 N-r4-(3-amino-6-bromo-lH-indazol-4-yl)phenyll-N'-(3-methylphenyl)urea and N-r4-(3-amino-4-bromo-lH-indazol-6-yl)phenyll-N'-(3-methylphenyl)urea
  • Example 167B 0.060g, 0.021 mmol
  • Example IB 0.073g, 0.21 mmol
  • the concentrate was purified by flash column chromatography on silica gel with methanol/dichloromethane (2:100 to 5:100), then purified by preparative HPLC with 30- 100% CH 3 CN/5 mM ammonium acetate buffer over 9 minutes to provide the desired products.
  • Example 167-1 LC/MS 434.2 (M-H) " , LC retention time 3.00 min.
  • Example 168 N-(4- ⁇ 3-amino-l-r2-(dimethylamino)ethyll-lH-indazol-4-yl)phenyl)-N'-(2-fluoro-5- methylphenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting N-(2- chloroethyl)-N,N-dimethylamine for 4-(2-chloroethyl)morpholine in Example 162.
  • Example 169B N-(4- ⁇ 3-amino-l-r2-(dimethylamino)ethyll-lH-indazol-4-yl)phenyl)-N'-(3- chlorophenyl)urea
  • the desired product was prepared as the bis(trifluoroacetate) salt by substituting Example 169A and N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]urea for Example 152B (50mg, 0.16 mmol) and Example 5 A, respectively, in Example 152C.
  • Example 170 A tert-butyl 2-(3-cyano-2-fluoro-4-iodophenoxy)ethylcarbamate The desired product was prepared by substituting tert-butyl 2-hydroxyethylcarbamate for 2-(4-morpholinyl)ethanol in Example 75 A.
  • R f 0.8 (1:1 ethyl acetate/hexanes).
  • Example 170B N-r2-(3-cyano-2-fluoro-4-iodophenoxy)ethyllmethanesulfonamide A mixture of Example 170A (317mg, 0.78 mmol) in TFA (1 mL) and CH 2 C1 2 (1 mL) was stirred at room temperature for 10 minutes and concentrated. The residue was partitioned between saturated NaHCO 3 and dichloromethane. The aqueous phase was extracted twice with dichloromethane and the combined organic extracts were dried (Na 2 SO 4 ), filtered, and concentrated.
  • Example 170C N- ⁇ 2-
  • the desired product was prepared by substituting Example 170B for 2-fluoro-6- iodobenzonitrile in Example 1 A.
  • Example 170D N- ⁇ 2-( ⁇ 3 -amino-4- ⁇ 4-( ⁇ r(2-fluoro-5 -methy lphenyl)aminol carbonyl) amino)pheny 11 - 1 H- indazol-7-yl)oxy)ethyllmethanesulfonamide
  • the desired product was prepared as the trifluoroacetate salt by substituting Example 170C for Example 152B in Example 152C.
  • the desired product was prepared by substituting 5-indolylboronic acid and Example IA for 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline and Example 15F, respectively, in Example 15G.
  • Example 162A A mixture of Example 162A (1.2 g, 3.1 mmol), l-bromo-2-methoxyethane (0.35 mL, 3.7 mmol) and K 2 CO 3 (857 mg, 6.2 mmol) in DMF (15 mL) wa stirred overnight at rt, then concentrated to dryness. The residue was partitioned between EtOAc and H 2 O. The extract was dried (Na2SO 4 ) and concentrated, and the residue was purified by flash chromatography on silica gel, eluting with 2% MeOH/CH 2 Ci 2 . The product was obtained as a mixture of Examples 172A and 172B (-3:1).
  • Example 172C and 172D 4-iodo- 1 -(2-methoxy ethyl) " 1 H-indazol-3 -amine and 4-iodo-2-(2-methoxyethyl) " 1 H-indazol-3 -amine
  • EtOH 10 mL
  • hydrazine monohydrate 0.58 mL
  • the mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel, eluting with 0-4% MeOH/ CH 2 C1 2 .
  • a mixture of isomers 172C and 172D was obtained.
  • MS (ESI(+)) m/e 317.8 (M+H) + .
  • Example 172E and 172F 4-(4-aminophenyl) " 1 -(2 -methoxy ethyl) " 1 H-indazol-3 -amine and 4-(4-aminophenyl) " 2-(2 -methoxy ethyl) " 1 H-indazol-3 -amine
  • a mixture of Examples 172E and 172F was prepared by substituting a mixture of Examples 172C and 172D for Example 15F in Example 15G.
  • MS (ESI(+)) m/e 283.0 (M+H) + .
  • Example 172G N- ⁇ 4-r3-amino-l-(2-methoxyethyl) " lH-indazol-4-yllphenyl)-N'-(2-fluoro-5- methylphenyl)urea
  • the desired product was obtained by substituting a mixture of Examples 172E and 172F for Example 15G and l-fluoro-2-isocyanato-4-methylbenzene for l-fluoro-3 -isocyanatobenzene in Example 15H. Additionally, DMF was used in place of CH 2 CI 2 . The mixture was concentrated and the residue was purified by preparative HPLC as in example 3 to provide the desired product as the trifluoroacetate salt.
  • Example 174 N-(4- ⁇ 3-amino-7-r2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-l-yl)ethoxyl-lH-indazol-4- yl)phenyl) " N'-(3,5-dimethylphenyl)urea
  • the desired product was prepared by substituting Example 145 A and l-isocyanato-3, 5- dimethylbenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • the product was purified by preparative HPLC as in example 3.
  • Example 175 N-r4-(3-amino-lH-indazol-4-yl) " 2,6-dimethylphenyll-N'-(2-fluoro-5-methylphenyl)urea
  • the desired product was prepared by substituting 4-bromo-2,6-dimethylaniline for 4-bromo- 2-ethylaniline in Examples 149A-C.
  • the desired product was prepared by substituting l-isocyanato-3 -(trifluoromethyl)benzene and 4-bromo-2,6-dimethylaniline for l-fluoro-2-isocyanato-4-methylbenzene and 4-bromo-2- ethylaniline, respectively, in Examples 149A-C.
  • Example 177 N-r4-(3-amino-lH-indazol-4-yl)phenyll-N'-(3-hydroxyphenyl)urea
  • the desired product was prepared by substituting 4-iodo- 1 -isocyanatobenzene and 3- hydroxyaniline for l-fluoro-2-isocyanato-4-methylbenzene and 4-bromo-2-ethylaniline, respectively, in Examples 149 A-C.
  • Example 178A N-(2- ⁇ P -amino-4-(4-aminophenyl) " 1 H-indazol-7-yll oxy ) ethyl)methanesulfonamide
  • the desired product was prepared by substituting Example 170C and 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline for Examples IA and IB, respectively, in Example IC.
  • Example 179 N- ⁇ 2-r(3-amino-4- ⁇ 4-r( ⁇ r2-fluoro-5- (trifluoromethyl)phenyll amino ) carbonyl)aminolphenyl ) - 1 H-indazol-7- yl)oxyl ethyl ) methanesulfonamide
  • the desired product was prepared by substituting Example 178 A and l-fluoro-2-isocyanato- 4-(trifluoromethyl)benzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 181 N- ⁇ 2-r(3-amino-4- ⁇ 4-r( ⁇ P-(trifluoromethyl)phenyllamino)carbonyl)aminolphenyl)-lH- indazol-7-yl)oxyl ethyl ) methanesulfonamide
  • the desired product was prepared by substituting Example 178 A and l-isocyanato-3 - (trifluoromethyl)benzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • Example 182C N-r4-(3-amino-lH-indazol-6-yl)phenyll-N'-(3-methylphenyl)urea
  • the desired product was prepared by substituting Example 182 A and IB for 1 A and 5 A respectively, in Example 5B.
  • Example 182 A was prepared by substituting Example 182 A for Example 1 A and 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline for Example 5A in Example 5B.
  • Example 183B 3 -amino-N-(3 -methy lphenyl)-6- ⁇ 4-( ⁇ ⁇ (3 -methy lphenyl)aminol carbonyl) amino)phenyl1- 1 H- indazole- 1 -carboxamide
  • the desired product was prepared by substituting example 183 A and l-isocyanato-3 - methylbenzene for 15G and l-fluoro-3 -isocyanatobenzene, respectively in example 15H. !
  • Example 184 N- P -(3 -amino- 1 H-indazol-4-yl)phenyl1 -N'-(3 -methy lphenyl)urea
  • Example 184A N-(3 -methylphenyl)-N'- ⁇ 3 -(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyllurea
  • the desired product was prepared by substituting 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)aniline for 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline in Example IB.
  • MS (ESI(+)) m/e 352.9 (M+H) + .
  • Example 185 A 4-iodo-7-methyl- 1 H-indazol-3 -amine The desired compound was prepared by substituting Example 15C for 2-fluoro-6- iodobenzonitrile in Example 1 A. MS (ESI(+)) m/e 273.8 (M+H) + .
  • Example 185B 4-(4-aminophenyl)-7-methyl- 1 H-indazol-3 -amine
  • the desired product was prepared by substituting Example 185A and 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline for Examples IA and IB, respectively, in Example IC.
  • MS (ESI(+)) m/e 239.0 (M+H) + .
  • Example 15H The desired product was prepared by substituting Example 185B and l-isocyanato-3 - methy Ibenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH 2 C1 2 .
  • Example 15H The desired product was prepared by substituting Example 185B and l-isocyanato-3 - (trifluoromethyl)benzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH 2 C1 2 .
  • Example 15H The desired product was prepared by substituting Example 185B and l-fluoro-2-isocyanato- 4-(trifluoromethyl)benzene for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH 2 C1 2 .
  • Example 189 N- f4-(3 -amino-7-methyl- 1 H-indazol-4-yl)phenyll-N'-(3 -bromophenyl)urea
  • the desired product was prepared by substituting Example 185B and l-bromo-3- isocyanatobenzene for Example 15G and l-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH 2 C1 2 .
  • Example 185B was prepared by substituting Example 185B for Example 15G in Example 15H. Additionally, DMF was used in place of CH 2 C1 2 .
  • Example 191 N- f4-(3 -amino-7-methyl- 1 H-indazol-4-yl)phenyll-N'-(2-fluoro-5-methylphenyl)urea
  • the desired product was prepared by substituting Example 185B and l-fluoro-2-isocyanato- 4-methylbenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH 2 C1 2 .
  • Example 192 N- r4-(3 -amino-7-methyl- 1 H-indazol-4-yl)phenyn-N'-(3 -cyanophenyl)urea
  • the desired product was prepared by substituting Example 185B and 3-isocyanatobenzonitrile for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H. Additionally, DMF was used in place of CH 2 C1 2 .
  • Example 193 N-r4-(3-amino-lH-indazol-4-yl)-2-(trifluoromethoxy)phenyll-N'-(2-fluoro-5- methylphenyPurea
  • the desired product was prepared by substituting 4-bromo-2-(trifluoromethoxy)aniline for 4- bromo-2-ethylaniline in Examples 149A-C.
  • Example 194 A N-(5-bromopyridin-2-yl)-N'-(2-fluoro-5-methylphenyl)urea
  • the desired product was prepared by substituting 2-amino5-bromopyridine and l-fluoro-2- isocyanato-4-methy Ibenzene for Example 15G and l-fluoro-3 -isocyanatobenzene, respectively, in Example 15H.
  • MS (ESI(+)) m/e 324.0 (M+H) + .
  • Example 194B N-r5-(3-amino-lH-indazol-4-yl)pyridin-2-yll-N'-(2-fluoro-5-methylphenyl)urea
  • the desired product was prepared by substituting Example 194A for Example 44A in Example 44B.
  • Example 195 A 7-fluoro-4-iodo- 1 H-indazol-3 -amine The desired product was prepared by substituting Example 26A for 2-fluoro-6- iodobenzonitrile in Example 1 A.
  • Example 195B N-r4-(3-amino-7-fluoro-lH-indazol-4-yl)phenyll-N'-r2-fluoro-5-(trifluoromethyl)phenyllurea
  • the desired product was prepared by substituting Example 195 A for Example IA and N-(2- fluoro-5-(trifluoromethyl)phenyl) " N , -[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyljurea for Example 5A in Example 5B.
  • Example 196 N-r4-(3-amino-7-fluoro-lH-indazol-4-yl)phenyll-N'-(4-fluorophenyl)urea
  • the desired product was prepared by substituting Example 195 A for Example 1 A and N-(4- fluorophenyl) " N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B.
  • Example 197 N- f4-(3 -amino-7-fluoro- 1 H-indazol-4-yl)phenyll -N'-(2-fluorophenyl)urea
  • the desired product was prepared by substituting Example 195 A for Example 1 A and N-(2- fluorophenyl) " N'-[4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyljurea for Example 5A in Example 5B.
  • Example 198 N-r4-(3-amino-7-fluoro-lH-indazol-4-yl)phenyll-N'-(3-fluoro-4-methylphenyl)urea
  • the desired product was prepared by substituting Example 195A for Example 1 A and N-(3- fluoro-4-methylphenyl) " N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyllurea for Example 5A in Example 5B.
  • Example 199 N-r4-(3-amino-7-fluoro-lH-indazol-4-yPphenyll-N'-phenylurea
  • the desired product was prepared by substituting Example 195 A for Example 1 A and N- phenyl-N'-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B.
  • Example 200A N- ⁇ 2- 1 " (3 -amino-4-iodo- lH-indazol-7-yl)oxylethyl) - 1,1,1 -trifluoromethanesulfonamide
  • the desired product was prepared by substituting trifluoromethanesulfonic anhydride for methanesulfonyl chloride in Example 170B.
  • Example 200B N- f2-( ⁇ 3 -amino-4- ⁇ 4-( ⁇ ⁇ (3 -methy lpheny Paminol carbonyl ) amino)phenyll - 1 H-indazol-7- yl ) oxy)ethyll -1,1,1 -trifluoromethanesulfonamide
  • the desired product was prepared by substituting Example 200 A and Example IB for Example 1 A and Example 5A, respectively, in Example 5B.
  • Example 201 N- F4-(3 -amino- 1 H-indazol-4-yl)-2-fluorophenyll-N'-(2-fluoro-5-methylphenyl)urea
  • the desired product was prepared by substituting l-fluoro-2-isocyanato-4-methylbenzene for l-isocyanato-3 -methylbenzene in Examples 44A-B.
  • Example 203 N- f4-(3 -amino- 1 H-indazol-4-y Pphenyl) -N'- r2-fluoro-3 -(trifluoromethyl)pheny llurea
  • the desired product was prepared by substituting N-(2-fluoro-3-trifluoromethylphenyl) " N'-[4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyljurea for Example 5A in Example 5B.
  • Example 204 N-r4-(3-amino-lH-indazol-4-yl)phenyll-N'-(4-bromo-2-fluorophenyl)urea
  • the desired product was prepared by substituting N-(4-bromo-2-fluorophenyl) " N'-[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5 A in Example 5B.
  • Example 205 N-r4-(3-amino-lH-indazol-4-yl)phenyll-N'-(5-fluoro-2-methylphenyPurea
  • the desired product was prepared by substituting N-(5-fluoro-2-methylphenyl) " N'-[4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyllurea for Example 5A in Example 5B.
  • Example 207A 2-fluoro-6-iodo-3-(3-morpholin-4-ylpropoxy)benzonitrile
  • the desired product was prepared by substituting 3-(4-morpholinyl) " propan-l-ol for 2-(4- morpholinypethanol in Example 75A.
  • MS (ESI(+)) m/e 391 (M+H) + .

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EP04776083A EP1638941B1 (en) 2003-05-22 2004-05-21 Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
DE602004027490T DE602004027490D1 (de) 2003-05-22 2004-05-21 Indazol-, benzisoxazol- und benzisothiazol-kinaseinhibitoren
SI200431481T SI1638941T1 (sl) 2003-05-22 2004-05-21 Inhibitorji indazol benzizoksazol in benzizotiazol kinaze
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BRPI0410745-4A BRPI0410745A (pt) 2003-05-22 2004-05-21 inibidores de indazol, benzisoxazol e benzisotiazol quinase
CN2004800205684A CN1826324B (zh) 2003-05-22 2004-05-21 吲唑、苯并异*唑和苯并异噻唑激酶抑制剂
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AU2004249675A AU2004249675B2 (en) 2003-05-22 2004-05-21 Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
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